JP2016503787A - Compositions comprising Raphanus, Theobroma and Passiflora for the treatment of opioid and alcohol abuse - Google Patents

Abstract

The present invention comprises: a) an extract of a plant belonging to the genus Raphanus, wherein said extract extracts at least aerial roots, seeds and / or bulbs using a hydrophilic, medium polarity and / or lipophilic solvent B) an extract of a plant belonging to the genus Theobroma, wherein said extract is obtained by extracting at least the fruit with a hydrophilic and / or moderately polar solvent And c) an extract of a plant belonging to the genus Passiflora, wherein said extract extracts at least flowers with a hydrophilic, moderately polar and / or lipophilic solvent A composition comprising, opioid abuse, opioid dependence, alcohol dependence and / or treatment of alcohol abuse Kicking use in their use, and / or an opioid and / or treatment of withdrawal symptoms of alcohol, as well as methods for their preparation. [Selection figure] None

Description

  The present invention relates to a) an extract of a plant belonging to the genus Raphanus, wherein said extract has at least air roots, seeds and / or bulbs hydrophilic, moderate polarity and / or parent B) an extract of a plant belonging to the genus Theobroma, wherein said extract is at least hydrophilic and / or moderate in fruit And c) an extract of a plant belonging to the genus Passiflora, wherein said extract is at least flower hydrophilic, Obtainable by extraction with moderately polar and / or lipophilic solvents A composition comprising, opioid abuse, its use in the treatment of opioid dependence, alcohol dependence and / or alcohol abuse, and / or in the treatment of opioid and / or alcohol withdrawal symptoms, and It relates to a method for its manufacture.

  In this specification, several documents including patent applications and manufacturer's instructions are cited. The disclosures of these documents are not believed to be related to the patentability of this invention, but are incorporated herein by reference in their entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

  Opioid and alcohol abuse is a complex disease characterized by a strong and sometimes uncontrollable desire for the latter, with compulsive drug search and use that persists even in the face of devastating consequences . Addiction is a brain disease that affects many brain circuits, including those involved in reward and motivation, learning and memory, and control of inhibitory behavior. Treatment is not simple because drug abuse and addiction have so many dimensions that it can disrupt so many aspects of an individual's life. Current practices for treating opioid and alcohol abuse include helping to control withdrawal symptoms during detoxification and help reestablish normal brain function and prevent recurrence And drug therapy to reduce desire. Currently, methadone, buprenorphine and naltrexone, for example for some people, are drugs for the treatment of opioid addiction. Acting on the same brain targets as heroin and morphine, methadone and buprenorphine suppress withdrawal symptoms and reduce desire. Naltrexone acts by blocking the action of heroin or other opioids at their receptor site and should only be used in patients who have already been detoxified. Due to compliance issues, naltrexone is not as widely used as other drug therapies. All drug therapies help patients free from drug discovery and related criminal behavior and become better able to accept behavioral treatments.

  Three drugs have been approved by the FDA for the treatment of alcohol abuse: naltrexone, acamprosate, and disulfiram. The fourth topiramate shows encouraging results in clinical trials. Naltrexone blocks opioid receptors involved in the rewarding effects of drinking and in the desire for alcohol. Acamprosate is believed to reduce prolonged withdrawal symptoms such as insomnia, anxiety, restlessness, and physical discomfort (such as an unpleasant or unpleasant emotional state such as depression, anxiety, or irritability). Disulfiram prevents alcohol breakdown and results in the accumulation of acetaldehyde, which in turn leads to very unpleasant reactions including flushing, nausea, and palpitation when the patient drinks alcohol. Although compliance can be a problem, disulfiram can be very effective among highly motivated patients.

  The technical problem underlying the present invention was to identify alternative and / or improved means and methods for treating opioid and alcohol abuse and symptoms of opioid and alcohol abuse.

  The solution to this technical problem is achieved by providing the embodiments characterized in the claims.

  Accordingly, the present invention provides, in the first aspect, a) an extract of a plant belonging to the genus Raphanus, wherein the extract contains at least aerial roots, seeds and / or bulbs with a hydrophilic, moderately polar and / or lipophilic solvent. And b) an extract of a plant belonging to the genus Theobroma, wherein said extract uses at least a fruit with a hydrophilic and / or moderately polar solvent Or obtained by extraction.

Dose-response effect on intraperitoneal administration of morphine or heroin of orally administered extract composition to re-establish motor behavior in rats. Each data point represents the mean (± SD) of 5 rats. ^* Significant difference between baseline and each treatment p <0.001; † Significant difference between that dose vs its lower dose (p <0.001). % Reduction in dependence on morphine or heroin after oral administration of the extract composition. Each data point represents the mean (± SD) of 5 rats. ^* Significant difference between baseline and each treatment p <0.001; † Significant difference between that dose vs its lower dose (p <0.001). HIC score for mice exposed to ethanol for 72 hours. Mice were treated with different doses of extract or vehicle at 1 and 4 hours and HIC scores were recorded over a 64 hour time course. HIC scores were significantly lower in the groups treated with 40 or 60 mg / kg extract for the first 12 hours (p <0.001). Short spindle spindle episode (BSE) activity was recorded in mice after chronic exposure to ethanol. Mice treated with 40 and 60 mg / kg extract composition have significantly less BSE than mice treated with vehicle from 2 to 72 hours after ethanol withdrawal. BSE activity for mice treated with 40 or 60 mg / kg extract composition was significantly lower than mice treated with vehicle (p <0.001).

  “Extracting” as used herein means the process of solubilizing compounds contained in the plant material to be extracted and the subsequent release of those compounds from said material. To do. The liberated compound can be referred to as an “extract” or can be obtained after subsequent processing, such as drying or addition of excipients, or form the basis of the resulting “extract” Can do. Methods for extracting plant material are well known in the art and are described, for example, in Gaedcke, Steinhoff, Herbal Medicinal Products, Medpharm Scientific Publishers, CRC Press 2003, ISBN: 0849310237. The extraction procedure can be based on various parameters such as weight, size or solubility / polarity depending on the targeted compound. The extraction according to the invention is based on solubility. Solubility describes the ability of a substance to dissolve in a solvent and is a function of temperature, pressure and polarity.

A “solvent” according to the present invention is a substance that has the ability to dissolve the compounds contained in the plant material to be extracted in order to obtain an extract as contained in the composition of the present invention. In other words, the solvent can dissolve the desired plant compound in the substrate plant material (also referred to herein as the drug that forms the extract) to form a solution containing the latter. The solvent is preferably a liquid, but can also be gaseous, eg, CO ₂ , or a solid, in which case it is liquefied for use in an extraction process as described herein. be able to. Solvents can be classified according to their polarity from polar (hydrophilic) to nonpolar (lipophilic). In general, polar solvents are believed to dissolve polar compounds best, while nonpolar solvents will best dissolve nonpolar compounds. The relative permittivity of the solvent can be used for the classification of the solvent into hydrophilic, medium polar or lipophilic solvents, but other means such as the Grunwald Winstein mY scale or the Koswer Z scale (Kosower, EM, “An introduction to Physical Organic Chemistry”, Wiley: New York, 1969, p. 293) can also be used for classification. In accordance with the present invention, the lipophilic solvent has a relative dielectric constant of less than 5, while the moderately polar solvent has a relative dielectric constant in the range of 5 to 20, and the hydrophilic solvent has a relative dielectric constant greater than 20. Have a rate.

  The hydrophilic solvent according to the invention can be, for example, polar branched or linear chain hydrocarbons, polar and medium polar organic compounds, chlorinated versions thereof, water or mixtures thereof. Preferably, the hydrocarbon has a C1-C10 framework, such as C1-C10 alcohols (eg n-butanol, isopropanol, n-propanol, ethanol or methanol) or acids (eg formic acid or acetic acid). . The polar organic compound is selected from the group consisting of acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO) or propylene carbonate.

  The moderately polar solvent according to the invention can be a moderately polar organic compound such as, for example, ethyl acetate, dichloromethane or tetrahydrofuran.

  Lipophilic solvents according to the invention can be, for example, nonpolar branched, aromatic or linear hydrocarbons or ethers (eg diethyl ether, 1,4-dioxane). Preferably, the hydrocarbon has a C1-C10 framework such as chloroform, toluene (also called toluol), benzene, cyclohexane, hexane, cyclopentane or pentane.

  Unless otherwise stated, regardless of the extraction method (see below), preferably a lipophilic or moderately polar solvent, more preferably a lipophilic solvent should be used as the solvent for the extraction of Raphanus plants It is.

  It is also preferred that the extraction be accomplished by leaching, cold soaking, decoction or digestion with the solvents described herein.

  Extraction procedures for leaching are well known in the art and contain a drug, i.e. the desired plant compound to be extracted, separated from the plant part when the solvent is poured over the plant part using the filter and contains the drug. The present invention relates to a process for extracting plants by capturing effluents. The yield of the extract is affected by the solvent (concentration, polarity, and quantity), extraction time, extraction flow and extraction equipment (volume, height of the batch). Extraction by leaching of a Raphanus plant, preferably Raphanus sativus species, or a mixture of Raphanus plants including plants of Raphanus satius species is preferably moderate, such as an ethanol / water mixture It is carried out using a polar solvent. Extraction by leaching of a Theobroma plant, preferably the Theobroma cacao species, or a mixture of Theobroma plants comprising the Theobroma cacao plant, is preferably, for example, a 20% acetone solution, water, methanol or water Is carried out using a hydrophilic solvent such as a methanol / methanol mixture.

  Cold soaking resulted in extraction of the liquid extract by soaking the base plant material in a solvent, optionally (sometimes) with shaking for a given period of time, such as 12-24 hours or more. An extraction procedure characterized by separation from plant material. In this procedure, the ratio of herbal medicine to extraction solvent is a relevant factor for the effectiveness of extraction. The amount of extractable material increases with the amount (mass, volume) of the extraction solvent because it reaches later in steady state conditions when larger amounts of extraction solvent are used. Thus, the ratio of herbal medicine to extraction solvent is a relevant parameter for the quality of the extract and should be defined to ensure batch-to-batch agreement. Extraction by rafting of a Raphanus plant, preferably Raphanus satius, or a mixture of Raphanus plants comprising a Raphanus satius plant, is preferably a moderately polar solvent such as, for example, an ethanol / water mixture It is implemented using. Extraction by cold immersion of a Theobroma plant, preferably the Theobroma cacao species, or a mixture of Theobroma plants comprising the Theobroma cacao plant, is preferably, for example, a 20% acetone solution, pure water, methanol or water / methanol It is carried out using a relatively hydrophilic solvent such as a mixture.

  Infusion is an extraction procedure characterized by boiling the basic plant material together with a solvent to the boiling point of the mixture. The extraction process generally takes a relatively long time compared to other extraction methods, particularly the extraction methods described herein. After boiling, the filtrate is separated from the used plant material. The amount of extractable material increases with the amount (mass, volume). Temperature and extraction time are additional parameters that can have an effect on the amount of natural extract. Extraction by decoction of a Raphanus plant, preferably a Raphanus satius species, or a mixture of Raphanus plants comprising a Raphanus satius plant, is preferably a moderately polar solvent such as, for example, an alcohol / water mixture It is implemented using. Extraction by decoction of a Theobroma plant, preferably the Theobroma cacao species, or a mixture of Theobroma plants comprising the Theobroma cacao plant, is preferably water or a low concentration alcohol / water or acetone / water mixture, for example. It is carried out using a hydrophilic solvent such as

  Digestion is an extraction procedure characterized in that a certain amount (mass / volume) of extraction solvent is used until a substance capable of extraction is completely transferred from the herbal matrix to the solvent. Thus, the ratio of drug extract can vary within a certain range from batch to batch. It is affected by herbal characteristics (extractable substance content, loss on drying, etc.). The herbal preparations produced by the leaching procedure are described by the average amount (mass / volume) of extraction solvent having a defined range, for example 1:12 (1:10 to 1:14). The dimension is either mass / volume of extraction solvent (m / v) or mass / mass (m / m). Extraction by digestion of a Raphanus plant, preferably a Raphanus satius species, or a mixture of Raphanus plants, including a Raphanus satius plant, is preferably a moderately polar solvent such as, for example, an alcohol / water mixture It is implemented using. Extraction by digestion of a Theobroma plant, preferably the Theobroma cacao species, or a mixture of Theobroma plants comprising the Theobroma cacao plant, is preferably water or a low concentration of alcohol / water or a low concentration of water. This is carried out using a hydrophilic solvent such as a / acetone mixture.

  The plant material used as the basis for the extraction process is preferably because fresh plant material contains water, which may promote hydrolysis of natural compounds and may destabilize the composition. It can also be plant material that is dry plant material but not treated or treated differently. In addition, and as is known in the art, the extraction efficiency is higher when the plant base material is crushed, chopped or pulverized, where the treatment of the latter plant material The degree of depends on the method chosen to extract the plant base.

  The genus Raphanus is a genus within the Brassicaceae family of plants. Currently and in accordance with the present invention, the genus includes the species Raphanus caudatus (sometimes also referred to as various R. satius), Raphanus raphanistrum and Raphanus satius, for example R . Raphanisturm subspecies landrum, R. Raphanisturm subspecies maritimus, “April Cross”, “Bunny Tail”, “Cherry Belle”, “Champion”, “Red "King (Red King)", "Sicily Giant", "Snow Bell", "White Icecle", "French Breakfast", "Plum "Purple Purple", "Black Spanish", "Black Spanish Round (Black Spanish Rou) d) ", or" it includes various artificial and natural variants such as radish "(R. Satiusu variant Rongipinatusu (longipinnatus)). According to the invention, it is preferred that at least air roots, seeds and / or bulbs are extracted. Preferably, only the latter plant parts are used as the basic plant material for extraction, and if more Raphanus plant parts are used, as many of the latter plant parts as possible are the basic plant material for extraction. Used as Preferably, when additional plant parts are used, the percentage of aerial roots, seeds and / or bulbs in the basic plant material is 50%, 60%, 70%, 80% of the basic plant material used for extraction, More preferably constitutes 85% and 90% or more (for each value) and most preferably more than 95%. It is therefore expected that additional plant parts and even whole plants can be extracted. Preferably, the Raphanus plant used to obtain the basic plant material is about 6-8 months old and / or harvested from April to May.

  Theobroma is a genus of plants in the family Malvaceae (also referred to as Sterculiaceae). At present and in accordance with the present invention, the genus includes the following species: Theobroma angustifolium, Theobroma bicolor, Theobroma cacao, Theobroma canumoma, Theobroma grandiflorum, Theobroma mammosum, Theoburo microobum (Theoburo micromum), Theobroma microbum, Theobroma oboum (Theobomao) heobroma speciosum), Theobroma Sutipuratsumu (Theobroma stipulatum), Theobroma Sabuinkanumu (Theobroma subincanum), Theobroma sylvestre (Theobroma sylvestre), Theobroma Bernoulli (Theobroma bernoulli), Theobroma Gireri (Theobroma gileri), Theobroma Guraukumu (Theobroma glaucum ), Theobroma hyraeum, Theobroma sinusum, Theobroma velutinum. In accordance with the present invention, artificial and natural varieties are also included. According to the invention, it is preferred that at least the fruit is extracted. Fruit includes, for example, seeds. Preferably, only fruits are used as the basic plant material for extraction, or as much as possible fruits are used as the basic plant material for extraction when additional Theobroma plant parts are used. Preferably, when additional plant parts are used, the percentage of fruit in the base plant material is 50%, 60%, 70%, 80%, more preferably 85% and 90% of the base plant material used for extraction. % Or more (for each value) and most preferably more than 95%. Thus, it is also expected that additional plant parts, such as leaves, bark, and even whole plants except roots can be extracted. Preferably, the Theobroma plant used to obtain the basic plant material is about 10-20 years old grown in a rainforest zone, for example West Africa or Central America, and / or harvested from April to May. The

  It is also envisaged to use plant parts of two or more different species of the genus defined herein as basic plant material for extraction. Preferably, and in the case of Rafanus, Raphanus satius or a mixture of plants of the genus Raphanus including plants of the species Raphanus satius are used as the basic plant material; in the case of Theobroma, A mixture of Theobroma plants, including plants, is used as the basic plant material.

  As mentioned above, the extract containing the solvent and the dissolved plant compound can generally be further processed according to the invention, for example to purify and concentrate the extracted compound. Concentration of the extracted compound can be accomplished, for example, by precipitation of the amount of solvent (s), e.g. by evaporating the solvent, e.g. Gaedcke, Steinhoff, Herbal Medicinal Products, Medpharm Scientific Publishers, CRC Press 2003, ISBN: 0849310237 Can be achieved by minimizing by other methods as described in. Purification can be accomplished, for example, by filtration, which is conveniently used before minimizing the amount of solvent, but not necessarily. Besides being a method for concentrating the extract, the precipitate can also be used as a means for purifying the extract, where the precipitate is the desired plant compound (s) or undesired Both can be impurities, both leading to the concentration and purification of a portion of the extract containing the desired compound (s). Preferably, the solution containing the desired plant compound (s) and solvent (s) is filtered and the filtrate is subsequently evaporated to dryness under vacuum. Selection of extraction process parameters (such as solvent selection) such that the filtration and the solvent evaporation are possible can be accomplished using standard procedures.

  Thus, preferably and generically, the extract according to the present invention extracts the (preferably dried) basic plant material using one or more solvents as defined herein. Subsequent subsequent filtration steps can be obtained or obtained by drying the filtered solution to obtain a dry extract.

  The dried extract can be further modified depending on the intended use, for example by adding excipients such as maltodextrin and / or silica for standardization purposes.

  In the case of extracts of plants belonging to the genus Raphanus, the extract is preferably 1% to 5% of total flavonoids, for example 1.1% to 4.9%, 1.2% to 4.8%, 25% to 4.75%, 1.5% to 4.5%, 1.75% to 4.25%, more preferably 2% to 3% or 2.25% to 2.75% total flavonoids It is standardized to contain. For example, the extract is 1%, 1.25%, 1.5%, 3.25%, 3.5%, 3.75%, 4%, 4.5%, or more preferably 2% It can be standardized to contain 3%, or most preferably 2.5% total flavonoids. In the case of an extract of a plant belonging to the genus Theobroma, the extract is preferably 3% to 20% of total procyanidins, such as 4% to 19%, 5% to 18%, 6% to 17% or 16%. Preferably, it is standardized to contain 6% to 14% or 15%, most preferably 7% to 12% or 13%, 8% to 10% or 11% total procyanidins. For example, the extract is 3%, 4%, 5%, 14%, 15%, 16%, 17%, 18%, more preferably 6%, 7%, 11% or 12%, most preferably 8 %, 9%, or 10% total procyanidins can be standardized. Those skilled in the art will be able to extract the extract to the values mentioned above by means known in the art and described herein, for example by adding excipients and / or adjusting the basic plant material. It is in a position to standardize.

  Combinations of extracts as defined herein have been shown to be well tolerated without side effects observed in in vivo studies.

  The present invention is based on the surprising discovery that the mentioned combinations of extracts can be used as pharmaceutical compositions to combat opioid and alcohol abuse and the symptoms of opioid and alcohol abuse. Specifically, we performed various tests with the compositions of the present invention in animal models suitable for evaluating the different effects of opioid and alcohol abuse. By evaluating the behavior of rats upon administration of the composition according to the invention in an intravenous self-administration model, it was possible to demonstrate that morphine and heroin self-administration was significantly reduced (Example 1). This evidence that the compositions of the present invention can effectively reduce the tonic activity indicates that the compositions are useful in the fight against opioid abuse. In addition, the ability of motor behavior is also implemented, which includes the appearance of hand tremor, memory ability, reaction time, hand-eye coordination, accuracy, balance, visual search, skill response, recognition, driving, number of periodic movements A scientifically accepted model for analyzing the effects of a given drug on (cycling times) and overall performance (see Example 2). In human subjects, the symptoms associated with alcohol abuse could be significantly reduced, thus demonstrating the effectiveness of treating alcohol abuse (see Example 4). Taken together, these results indicate that the compositions of the present invention are suitable for reducing the urge to administer alcohol or opioids and to minimize the symptoms associated with withdrawal of alcohol and opioids. It shows that. None of the plants alone have been previously described in this context.

  The following summarizes the knowledge of Raphanus and Theobroma plants and their potential importance in medical scenarios. In terms of ingredients, plants of the genus Theobroma are known to contain high concentrations of tannins and flavonoids such as procyanidins and other phenolic compounds such as flavonoids. In theobroma cacao, flavonoid antioxidants have been shown to lower cholesterol levels by preventing cholesterol from collecting in the blood vessels. In addition, the antioxidant is thought to support cardiac function. Studies have shown that blood vessels are more relaxed by their antioxidants, effectively lowering blood pressure and increasing circulation (Ding et al., Nutr Metab (Lond), 3: 2 (2006); Khawaja et a., Curr Atheroscler Rep., 13: 447-452 (2011)).

  Theobroma cacao also contains arginine, an amino acid that helps muscle build and also promotes faster recovery after exercise. The benefits of arginine in this process allow for faster recovery. Arginine is called the 'sexual desire promoting' component and gives a relaxed feeling and reduces stress. Theobroma cacao as well as other Theobroma species include a variety of additional compounds with mood effects such as MAO inhibitors (monoamine oxidase enzyme inhibitors), anandamide, tyramine, serotonin, phenylethylamine (PEA) . These mood enhancers are believed to motivate energetic and happy feelings and personal improvements such as exercise and weight loss. Xanthine derivatives such as caffeine and theobromine have also been found in theobroma cacao. These give energy and are maintained rather than temporary jolts that can make a person irritable. Caffeine and theobromine also provide bark and concentration throughout the day. In addition, a strong appetite suppressant calms the strong desire to make dieting difficult. Chocolate is known to increase the levels of neurotransmitters such as phenylethylamine, serotonin, and anandamide in the brain. Imbalances in various neurotransmitters including serotonin have also been reported in subjects with CFS (chronic fatigue syndrome). The effects of cocoa in subjects with chronic fatigue syndrome have not been studied to date. It has been hypothesized that chocolate can reduce the burden of CFS symptoms by modulating neurotransmitters (di Tomaso et al., Nature, 382, 677-678 (1996)). The relationship between chocolate and mood is very complex, combining the psychopharmacological components, the nutritional and sensory characteristics of the food. Individual and situational differences in chocolate consumption may also affect mood, and mixed results in previous studies indicate that the direction of the relationship remains unclear (Macht M. and Mueller J, J Nerv Ment Dis., 195 (12): 1024-6 (2007)). Theobroma cacao is also considered one of the best food sources of magnesium.

  It has been shown that cocoa intake can reduce the titer of certain IgG2a, IgG2b and IgG2c. In addition, cocoa ingestion in CIA (collagen-induced arthritis) rats reduces ROS (reactive oxygen species) production, TNFα and NO (carbon monoxide) release from peritoneal macrophages, and Th in ILN (inguinal lymph nodes). : Reduced cytotoxic T cell ratio. Diet enriched with cocoa flavonoids in LOU rats with CIA had no effect on hind limb swelling but was able to modulate specific antibody responses (Ramos-Romero S., et al., Br J). Nutr, 107 (3): 378-87 (2012)).

  The inhibitory effect of PCE (polyphenol-enriched cocoa extract) on acute UC (ulcerative colitis) induced by DSS was attenuated by oral administration of PCE obtained from cocoa. This effect is mainly due to inhibition of transcription factors STAT1 and STAT3 in enterocytes, and it has been shown that inhibition of NF-κB is also related (Andujar et al., Oxidative Medicine and Cellular Longevity, Vol. 2012). : 1-23 (2012)). Moreover, LCC (liquid column chromatography) of cacao mass has been shown to have anti-HIV activity (Sakagami H. et al., In Vivo, 25 (2): 229-36 (2011)).

  It is known in the art that the roots and leaves of Raphanus plants contain alkaloids, proteins, polysaccharides, flavonoids, glycosides, and phenolic compounds. It has been hypothesized that the biological activity of cruciferous vegetables is due to metabolites of a class of phytochemicals called glucosinolates. The chemical properties of these metabolites, including isothiocyanates, determine the biological activity of these compounds and hence their effects on human health (Gutierrez RM and Perez RL, Scientific World Journal, 4: 811-837 (2004)). R. HPLC identification of polyphenols in Satius leaves showed the presence of catechin, protocatechuic acid, syringic acid, vanillic acid, ferulic acid, sinapic acid, o-coumaric acid, myricetin, and quercetin in leaves and stems (Beevi et al., Plant Foods Hum Nutr., 65 (1): 8-17 (2010); Beevi et al., Nat Prod Res., 26 (6): 557-63 (2012)).

Among the different extraction solvents, the leaf and stem methanol extracts showed strong reducing ability, significantly inhibited the peroxidation of linoleic acid, and showed metal chelating activity. Furthermore, they have an IC ₅₀ (half inhibition of 31 and 42 μg / ml for DPPH radicals, 23 and 52 μg / ml for superoxide radicals, 67 and 197 μg / ml for hydrogen peroxide, and 56 and 62 μg / ml for nitric oxide. Each of the free radicals was effectively trapped at the concentration). The leaves show the strongest antioxidant and radical scavenging activity compared to the stem, which can be explained by the high polyphenol content. Thus, R.I. Satius leaves and stems (often a poorly utilized part of this vegetable) had significant amounts of polyphenols.

  Extracted using different polar solvents. The effectiveness of different parts of Satius, such as different parts of roots, stems and leaves, was tested (Beevi et al., Plant Foods Hum Nutr., 65 (3): 200-9 (2010)). The molecular mechanisms leading to growth arrest and apoptotic cell death in human cancer cell lines were investigated. R. Satius showed a chemopreventive and significant antiproliferative effect of hexane extract. R. Raphasatin isolated from Satius activated the antioxidant response element (ARE) in the stably transfected reporter cell line, but not its degradation product. Mice that were fed a diet consisting of 20% lyophilized radish for 2 weeks were significantly higher in the liver than the mice fed the nutritionally matched control diet. And expression of glutathione S-transferase α2 (Scholl et al., J Food Sci., 76 (3): C504-11 (2011)).

  R. An aqueous extract of Satius bark was tested for its anti-urinary calculus and diuretic activity (Vargas et al., Journal of Ethnopharmacology 68, pp. 335-338 (1999)). A significant decrease in stone weight compared to the control group was observed after treatment in animals given the aqueous extract. This extract showed an increase in urine volume at 24 hours when compared to the control.

  R. The antidiabetic effect of Satius could be further studied and shown to be able to reduce blood glucose levels (Shukla et al, Pharm Biol., 49 (1): 32-7 (2011)).

  A surprising finding is the ability of Raphanus extracts to regulate brain dopamine levels. In the scientific community, the rewarding effects of many abused drugs are mediated to some extent all by the mesolimbic dopaminergic pathway that occurs in the ventral tegmental area and innervates the septal nucleus accumbens It is assumed that. Depending on different metabolism, opioids, stimulants, ethanol and nicotine all increase extracellular levels of dopamine in the septal nucleus. While not limited to a particular scientific theory regarding the action of the composition of the invention, on the other hand, consistent with the demonstrated anti-addictive action of the aforementioned composition of the invention, in the septal nucleus accumbens It could be shown that the release of dopamine can be reduced (even within the first 2 hours of administration; data not shown). On the other hand, as can be seen from Example 5 below, it was also possible to demonstrate that Raphanus extracts resulted in an increase in dopamine within 30 minutes after administration. An increase in dopamine levels is also beneficial in the treatment of drug addiction as defined herein below, for example in the treatment of depression aspects associated with opioid / alcohol addiction and / or opioid / alcohol withdrawal. Therefore, modulation of brain dopamine levels is beneficial in the treatment of drug addiction and in the treatment of withdrawal symptoms as defined herein below.

  As outlined herein above, currently possible treatments for drug abuse target specific abused drugs or classes of drugs. However, the compositions of the present invention are effective in the treatment of many forms of drug abuse, i.e. opioid and alcohol abuse, and in the treatment of opioid and alcohol withdrawal symptoms. Furthermore, the compositions of the present invention are believed to act on several receptors, such as opioid receptors, and exhibit synergism overall. They also reduced essentially all or at least the main symptoms of opioid and / or alcohol withdrawal and had sedative and antidepressant activity while having fewer side effects.

In a preferred embodiment of the composition of the present invention, the solvent of a) is selected from the group consisting of water, alcohol, water / alcohol mixture, ketone, water / ketone mixture, CO ₂ , ethyl acetate, hexane and chlorinated forms thereof. And / or the solvent of b) above is selected from the group consisting of water, alcohols, water / alcohol mixtures, ketones and water / ketone mixtures.

  The alcohols that can be used according to this preferred embodiment are preferably selected from the group consisting of methanol, ethanol, butanol, propanol, isopropanol, propylene glycol, glycerol and combinations thereof. Preferably, methanol or ethanol is used as the solvent either alone or in combination with, for example, 30% methanol and 70% ethanol. Alcohols, in particular the alcohols of the aforementioned group, can also be used as solvents in the respective mixing with water, ie the solvent is a water / alcohol mixture. Preferably, the percentage of alcohol in the corresponding mixture is 25% to 95%, such as 30% to 90%, 40% to 80%, 50% to 70%, 30%, 50% or 70%, but more High and lower alcohol percentages are also expected, eg 10%, 15%, 20%, 80% or 90%. Preferably, an ethanol / water mixture containing 30% to 90%, 40% to 80%, 50% to 70%, 30%, 50% or 70% ethanol, or 30% to 90%, 40% to 80%, A methanol / water mixture containing 50% to 70%, 30%, 50% or 70% methanol is used as the solvent.

  The ketones that can be used according to the present invention are preferably selected from the group consisting of acetone and butanone (also known as methyl ethyl ketone). Preferably, acetone is used as the solvent. Ketones, in particular the aforementioned group of ketones, can each also be used as a solvent in mixing with water, ie the solvent is a water / ketone mixture. Preferably, the percentage of ketone in the corresponding mixture is 25% to 95%, such as 30% to 90%, 40% to 80%, 50% to 70%, 30%, 50% or 70%, but more High and lower ketone percentages, such as 10%, 15%, 20%, 80% or 90% are also expected. For example, Theobroma plants can be extracted with a ketone / water mixture of 10% or 20% ketone. Preferably, an acetone / water mixture containing 30% to 90%, 40% to 80%, 50% to 70%, 30%, 50% or 70% acetone is used.

  Ethyl acetate is a moderately polar solvent (also referred to in the art as a polar aprotic solvent) according to the definition given hereinabove. Preferably, ethyl acetate is used at a temperature of 40-60 ° C, more preferably in combination with low pressure.

  Hexane is a nonpolar solvent according to the definition given hereinabove. Preferably, hexane is used at a temperature of 40-60 ° C, more preferably in combination with low pressure.

CO ₂ is a non-polar solvent according to the definition given hereinabove and is in a fluid state when it is kept at its critical temperature and pressure, and in the art it is supercritical CO ₂ (also referred to as scCO ₂ Also known as). Standard conditions for temperature and pressure for CO ₂ extraction are pressures of 300-400 bar and temperatures of 30-50 ° C. in very small amounts of liquid solvents (eg He et al., Int J Mol Sci., 13 (10): 13065-78 (2012)).

  In a further preferred embodiment of the composition according to the invention, said extract of a) having a drug-extract ratio of 4 to 7.5: 1 and said b having a drug-extract ratio of 3 to 8: 1. ) Extract of about 1.5 to about 6.5 parts of the extract of a) and about 3.5 to about 7.5 parts of the extract of b) Exists.

  “Drug-extract ratio” (sometimes abbreviated DER) is a well-known parameter in the art and is the basis plant material (including the desired plant compound to be extracted) used in the manufacture of plant extracts. Refers to the ratio between the amount and the amount of dry plant extract obtained, wherein the dry plant extract is not mixed with further substances such as excipients, but of endogenous plant compounds. On extracts (eg “Fundamentals of Pharmacognosy and Phytotherapy” by Michael Heinrich, Joanne Barnes, Simon Gibbons, Elizabeth M. Williamson, Elsevier Science, 1st edition, 2004, ISBN: -10: 0443071322, Chapter 9, P. 144 -159). The number written before the colon is the relative amount of the basic plant material, while the number written after the colon is the relative amount of the dried plant extract obtained. The person skilled in the art will adjust the various parameters of the extraction process such as solvent, temperature, extraction method, etc. to achieve the drug-extract ratio as specified herein for each plant extract. It is in a position to make adjustments using one's common knowledge or standard experiments (see also, for example, “Fundamentals of Pharmacognosy and Phytotherapy” above). For example, an extract of Raphanus having a drug-extract ratio of 4 to 7.5: 1, such as an extract of Rafanus satius, is a medium polar and / or lipophilic solvent (eg 50% water / ethanol mixture) ) And / or by using cold immersion as an extraction method. Without limitation, theobroma extracts having a drug-extract ratio of 3-8: 1, such as extracts of theobroma cacao, are hydrophilic and / or moderately polar solvents (eg 10% or 20% By using ethanol / water mixtures or solvents such as 10% or 20% acetone / water mixtures or 40-60% ethanol / water or 40-60% acetone / water mixtures) and / or as an extraction method. In some cases, for example, when ethanol is used as a solvent, it can or can be obtained using a temperature below 40 ° C.

  The term “about” as used herein in terms of numerical values, especially when used in the context of the ratio of various extracts to each other when included in a composition of the present invention, is up to +/− 10%, preferably +/−. It is meant to refer to an average deviation of 5%, for example +/− 2.5%, +/− 1.25% or +/− 0.625%. At the same time, the designation also refers to said numerical value without the term “about”, eg the mentioned ratio value, ie the designation also refers to said ratio value itself without taking into account the mean deviation.

  In the context of the relative amounts of extracts a) and b) relative to each other, i.e. the ratio in which they are present in the composition, the term "parts" refers to mass / mass (abbreviated m / m) or volume / volume ( (Abbreviated as V / V).

  More preferably, the ratio of extract a) to extract b) (written in the form (a): b)) is 2-6: 4-7 (ie 2-6 parts of extract a): 4- 7 parts of extract b)), selected from the group consisting of 3-5: 4-6. Even more preferred is a ratio of 4-5: 1.

  In another preferred embodiment of the composition according to the invention, the composition further comprises c) an extract of a plant belonging to the genus Passiflora, wherein said extract has at least its flowers hydrophilic, moderate polarity and / or And / or obtained by extraction with a lipophilic solvent; and / or d) an extract of a plant belonging to the genus Crocus, wherein said extract has at least its flowers hydrophilic, moderate polarity and And / or obtained by extraction with a lipophilic solvent.

  The genus Passiflora is a genus in the family of Passifloraceae. Said genus includes more than 500 species. In accordance with the present invention, artificial (horticultural hybrids) and natural varieties are also included. According to the invention, it is preferred that at least flowers are extracted. Preferably, only the latter plant parts are used as the basic plant material for extraction, or if more plant parts are to be used, as many latter plant parts as possible are the basis for extraction. Used as plant material. Preferably, when additional plant parts are used, the percentage of flowers in the basic plant material is 50%, 60%, 70%, 80%, more preferably 85% and 90% of the basic plant material used for extraction. % Or more (for each value) and most preferably more than 95%. It is therefore expected that additional plant parts and even whole plants can be extracted. Preferably, the parts of the plant, in particular the flowers, should preferably be harvested from a specimen of at least 3 years old after the Passiflora plant has formed cocoons in the spring. It is also preferred that the plants of the genus Passiflora cultivated on preferably drained soil in Brazil are harvested.

  The following provides a summary of current knowledge regarding the components and characteristics of the plants of the genus Passiflora. Many species have been found to contain beta-carboline harmala alkaloids, which are MAO inhibitors with antidepressant properties. Although its flowers and fruits have only trace amounts of these chemicals, leaves and roots are often more powerful and have been used to enhance the action of drugs that change the mind. The most common of these alkaloids is Harman (1-methyl-9H-b-carboline), but Harmarin (4,9-dihydro-7-methoxy-1-methyl-3H-pyrido [3,4] -B] indole), harmalol (1-methyl-2,3,4,9-tetrahydropyrido [3,4-b] indole-7-one), harmine (7-methoxy-1-methyl-9H-) Pyrido [3,4-b] indole) and Halmol have also been identified. Apigenin, benzoflavone, homoorientin, 7-isoorientin, isoshaftside, isovitexin (or saponaretin), kaempferol, lusenin, luteolin, n-orientin, passifflorine (named after its genus) A number of flavonoids and their glycosides have been found in the genus Passiflora, including quercetin, rutin, saponarine, shaftside, vicenin and vitexin. Maypop, Blue Passion Flower (P. caerulea), and perhaps others, are flavones with proven anxiolytic and anti-inflammatory, suspected aromatase inhibitor properties Containing chrysin. It is also the hydrocarbon nonacosane and anthocyanidin pelargonidin-3-diglycoside that are documented to be present in large quantities in at least some Passiflora species. With respect to organic acids, the genus is rich in formic acid, butyric acid, linoleic acid, linolenic acid, malic acid, myristic acid, oleic acid and palmitic acid and phenolic compounds, and the amino acid α-alanine. Esters such as ethyl butyrate, ethyl caproate, n-hexyl butyrate and n-hexyl caproate give their fruits a flavor and a palatable odor. The most important sugars contained in the fruits are D-fructose, D-glucose and raffinose. Among the enzymes, the species of the genus Passiflora was found to be rich in catalase, pectin methylesterase and phenolase.

  Various components of the plants of the genus Passiflora have been shown to have a variety of therapeutically useful effects, such as laid out below. Fresh or dried flowers of various Passiflora species are used to make tea, it is used to treat insomnia, hysteria, and epilepsy and is also highly appreciated for its analgesic properties Yes. P. P. edulis (passion fruit) and a few other species are used for similar purposes in Central and South America. Once dried, the leaves can be smoked. Only a very small number of species of the genus Passiflora have been scientifically studied. In the first study on the treatment of generalized anxiety disorder, the Maypop extract performed as well as oxazepam, but had fewer short-term side effects. Follow-up by a long-term study was recommended (Akhondzadeh et al., Journal of Clinical Pharmacy and Therapeutics, vol. 26, issue 5, p. 363-367, (2001)). Passiflora incarnata has been recorded in the pharmacopoeia of the UK, USA, India, France, Germany, Switzerland and other countries (Dhawan et al., J Ethnopharmacol.; 78 (2-3): 165 -70 (2001)). The active ingredient responsible for the potential medicinal action is not definitive (Carlini EA, Plants and the central nervous system. Pharmacology, Biochemistry and Behavior. 2003; 75: 501-512). Most available data suggest that flavonoids are potential active ingredients (Speroni and Minghetti, Planta Med .; 54 (6): 488-91 (1988); Dhawan et al. , J Ethnopharmacol.; 78 (2-3): 165-70 (2001); Dhawan et al., J Pharm Pharmaceut Sci., 6 (2): 215-222 (2003)).

  Studies in animal models have demonstrated efficacy against pentylenetetrazole (PTZ) -induced seizures of extracts of the genus Passiflora and flavonoid fractions (Speroni and Minghetti, Planta Med.,; 54 (6): 488-91 (1988); Speroni and Billi, Phytotherapy Research, 10: S92-S94 (1996); Nassiri-Asl et al., BMC Complement Altern Med., 8; 7: 26 (2007); Nassiri-Asl et al Progess in Neuro-Psychopharmacology and Biological Psychiatry, 32: 989-993 (2008)). In three clinical trials, the extract of the genus Passiflora showed anxiolytic efficacy. One of the trials compared Passiflora to placebo (Movafegh et al., Anesth Analg., 106 (6): 1728-32 (2008)), and two other studies showed that Passiflora was benzodiazepine. (Mori et al., Rinsho Hyoka [Clinical evaluation for drugs], 21 (3): 383-440 (1993); Akhondzadeh et al., J Clin Pharm Ther ., 26 (5): 363-7 (2001)). In addition, the extract of the genus Passiflora showed sedation in two clinical trials (Akhondzadeh et al., J Clin Pharm Ther., 26 (5): 369-73 (2001); Movafegh et al., Anesth Analg., 106 (6): 1728-32 (2008)). The results of the study (Singh et al., Journal of Ethnopharmacology, Volume 139, issue 1, p. 273-279 (2012)) show that the hydroethanolic extract of Passiflora incarnata exhibits PTZ-induced seizures. We conclude that diazepam, a standard antiepileptic drug, suppresses and improves its related post-seizure depression that is known to be exacerbated. Oral preoperative administration of Passiflora incarnata suppresses increased anxiety before spinal anesthesia without altering sedation level or hemodynamics as a result of psychomotor function tests. Harmin and Harman, the effective alkaloids in passionflower, affect the level of GABA, a neurotransmitter targeted by benzodiazepines such as Valium and Xanax. Recently, the value of passion flower in the treatment of opiate withdrawal symptoms has become apparent. According to the National Institutes of Health, the use of passion flower with clonidine during opiate withdrawal results in better symptom relief than with clonidine alone. Although further research is needed, it is believed that according to the present invention, especially the relaxing properties of passionflower may be useful in alleviating the symptoms of opioids and alcohol withdrawal.

  The genus Crocus is a genus in the family Iridaceae and subfamily Crocoideae. Various species exist and are well known to those skilled in the art. These species are in accordance with Mathew (Brian Mathew, Crocus: A Revision of the Genus Crocus, Timber Press, 1983. ISBN 0-917304-23-3). , Versicolores, Longiflori, Kotschyani, Crocus clauses including Crocus; and ii) Series Reticulati, Biflori, Oseri, p ), Flavi, Aleppici, Carpetani, Intertexti and Laewigata (La can be categorized into Nudiscapus clauses, including evigatae). According to the invention, it is preferred that at least flowers are extracted. Preferably, only the latter plant parts are used as the basic plant material for extraction, or if more plant parts are to be used, as many latter plant parts as possible are the basis for extraction. Used as plant material. Preferably, when additional plant parts are used, the percentage of flowers in the basic plant material is 50%, 60%, 70%, 80%, more preferably 85% and 90% of the basic plant material used for extraction. % Or more (for each value) and most preferably more than 95%. It is therefore expected that additional plant parts and even whole plants can be extracted. The plant parts, especially flowers, are preferably harvested from plants cultivated in Greece, Spain and Iran, and in countries with an average annual rainfall of 400-1000 mm. Abundant vermicelli and a drier summer are optimal. Planting is preferably done in June, and harvesting is a quicker work if necessary: after flowering at dawn, the flowers rapidly shrink as the day passes. All plants will flower within a period of 1 or 2 weeks.

  The following provides a summary of current knowledge about the constituents and characteristics of the plants of the genus Crocus: a well-known spice derived from Crocus satius in view of its wide range of medical uses known today Extensive phytochemical and biochemical for saffron (see eg Negbi, M. (Editor), Saffron: Crocus sativus L., CRC Press (1999), ISBN: 987-90-5702-394-1) Research has been conducted and various biologically active components have been isolated. Saffron contains more than 150 volatile and fragrant compounds. Characteristic components of saffron are crocin (causes color), picrocrocin (causes bitterness), and safranal (causes odor and aroma). It also has many non-volatile active components, many of which are carotenoids, including zeaxanthin, lycopene, and various α- and β-carotenes. Volatile substances with a very strong odor are composed of more than 34 components, which are mainly terpenes, terpene alcohols and their esters. Non-volatile materials include 14 crocins, including carotenes, crocetin, the bitter substance picrocrocin (safranal's glycoside precursor) and the main sensory stimulating principle of stigma, safranal. Causes of red or reddish brown. However, the saffron bright yellow to orange color is mainly due to α-crocin. This crocin is trans-crocetin di- (β-d-gentiobiosyl) ester. Tissue (IUPAC) name: 8,8-diapo-8,8-carotene acid. This means that crocin, the basis of the saffron fragrance, is the digentiobiose ester of carotenoid crocetin. Crocins themselves are a series of hydrophilic carotenoids that are either monoglycosyl or diglycosyl polyene esters of crocetin. Crocetin is a conjugated polyene dicarboxylic acid that is hydrophobic and therefore oil soluble. When crocetin is esterified with two water-soluble gentiobioses (which are sugars), it results in a product that is itself water-soluble. The resulting α-crocin is a carotenoid pigment that may contain more than 10% dry saffron mass.

  C. Satius has been shown in the art to have an antidepressant effect, and two effective antidepressant ingredients are crocin and safranal. Preliminary phytochemical results showed that the anti-nociceptive and anti-inflammatory effects of petal extracts may be caused by their flavonoids, tannins, and anthocyanins content Could be suggested. Other studies have demonstrated the existence of various flavonoids such as rutin, quercetin, luteolin, hesperidin, and bioflavonoids (Srivastava et al., Pharmacogn Rev., 4 (8): 200-8 ( 2010)).

  Fatehi et al. (J Ethnopharmacology, 84: 199-203 (2003)) The effect of Satius petal extract on blood pressure in anesthetized rats was examined, and the effect of isolated rat vas deferens and guinea pig ileum responses induced by electrical field stimulation (EFS) was also investigated. C. Satius petal water and ethanol extracts reduced blood pressure in a dose-dependent manner.

  In one of its studies, C.I. The anticonvulsant activity of safranal and crocin, constituents of the Satius stigma, was evaluated in mice using pentylenetetrazole (PTZ) induced convulsions in mice. Safranal (0.15 and 0.35 ml / kg body weight, ip) reduced the duration of seizures, delayed the onset of tonic convulsions, and protected mice from death. Crocin (22 mg / kg body weight, ip) showed no anticonvulsant activity.

  C. Satius ethanol extract and safranal have been shown to reduce the number of coughs (Hosseinzadeh et al., Fitoterapia, 77: 446-8 (2006)).

  Another study is C.I. Satius L. Treatment with crocins has been shown to induce anxiolytic-like effects in rats (Pitsikas et al., Phytomedicine, 15: 1135-9 (2008)).

C. To study the mechanism (s) of Satius' relaxation, the stimulatory effect of β-adrenergic receptors on the tracheal chain of this plant's aqueous-ethanolic extract and one of its constituents, safranal, guinea pig Was investigated. The result is C.I. The extract from Satius shows a relatively strong stimulatory effect on the β ₂ -adrenergic receptor, partly due to its constituent safranal. A potential inhibitory effect on the plant histamine (H ₁ ) receptor was also suggested in the art (Nemati et al., Phytomedicine, 15: 1038-45 (2008)).

  C. The efficacy of Satius petals was evaluated in the treatment of mild to moderate depression in a 6-week, double-blind, placebo-controlled randomized trial. The results of this study show C.I. in the treatment of mild to moderate depression. It shows the effectiveness of Satius petals. In further preliminary studies, saffron was compared to the drug fluoxetine; saffron was found to perform as well as the drug in treating depression (Moshiri et al., Phytomedicine, 13: 607-11 (2006 )).

  In another study, saffron extracts and two of its main components, crocin and crocetin, improved memory and learning skills in ethanol-induced learning behavioral disorders in mice and rats. It has been hypothesized in the art that oral administration of saffron is useful in the treatment of neurodegenerative disorders and related memory disorders. Therefore, it has been claimed in the art that the use of these substances is useful in pharmacological alleviation of cognitive impairment (Sigiura et al., Phytother Res., 9: 100-4 (1995)).

  Further studies show that crocin analogs isolated from saffron significantly increase blood flow in the retina and choroid, promote retinal function recovery, and prevent it from ischemic retinopathy and / or age-related macular degeneration It has been shown that it can be used to treat (Xuan B., J Ocul Pharmacol Ther, 15: 143-52 (1999)).

  Another study (Ghoshooni et al., Pak J Biol Sci., 14 (20): 939-44 (2011)) related to the ethanol extract of saffron and its constituent safranal. This study was an investigation into the acquisition and expression of morphine-induced place preference (CPP) in male Swiss Webster mice (20-25 g). An unbiased place conditioning method was applied to evaluate the reward characteristics of morphine. Saffron extract and safranal were administered intraperitoneally (ip) during (acquisition) or after induction (expression) of morphine CPP. In a pilot study, the extract and safranal were administered to the animals alone to assess whether they had any reward characteristics. Subcutaneous injection (sc) of morphine (4 and 8 mg kg (-1)) and extract (50 mg kg (-1); ip) induced CPP. Extracts (10, 50 and 100 mg kg (-1); ip) reduced morphine CPP acquisition and expression. The same results were obtained with safranal (1, 5 and 10 mg kg (-1), ip). It can be concluded that both ethanolic saffron extract and safranal can inhibit morphine-induced CPP acquisition and expression in mice.

  As is apparent from the above and is not bound by any particular theory, the antidepressant, relaxing and potential effects, particularly those associated with CPPs of the plants of the genus Crocus, are Raphanus and Theobroma And optionally when used as part of a composition according to the present invention comprising an extract of the genus Passiflora.

The solvent definitions, combinations and specific examples described herein above apply mutatis mutandis to this preferred embodiment for the extraction of Passiflora and Crocus unless otherwise specified. Thus, the solvents of said c) and d) are preferably selected from the group consisting of water, alcohols, water / alcohol mixtures, ketones, water / ketone mixtures, CO ₂ , ethyl acetate, hexane and their chlorinated forms. The More preferred is the use of ethanol as a solvent for the extraction of Passiflora and any of the aqueous solvents described hereinabove for the extraction of Crocus, such as a water / ethanol mixture. It is also preferred that the extraction is carried out by leaching or cold soaking.

  In the case of an extract of a plant belonging to the genus Passiflora, the extract is preferably 1% to 5% total flavonoids, for example 1.1% to 4.9%, 1.2% to 4.8%, 1.25% to 4.75%, 1.5% to 4.5%, 1.75% to 4.25%, more preferably 1.5% to 3% or 1.5% Standardized to contain ~ 2.5% total flavonoids. For example, the extract is 1%, 1.25%, 1.5%, 3.25%, 3.5%, 3.75%, 4%, 4.5%, or more preferably 1.75. %, 2.5% or most preferably 2% total flavonoids.

  In the case of an extract of a plant belonging to the genus Crocus, the extract is preferably 1% to 5% safranal, for example 1.1% to 4.9%, 1.2% to 4.8%, 1.25% Contains 4.75%, 1.5% to 4.5%, 1.75% to 4.25%, more preferably 1.5% to 3% or 1.5% to 2.5% safranal To be standardized. For example, the extract is 1%, 1.25%, 1.5%, 3.25%, 3.5%, 3.75%, 4%, 4.5%, or more preferably 1.75. %, 2.5% or most preferably 2% safranal.

  In a more preferred embodiment of the composition according to the invention, the extract of a) above having a drug-extract ratio of 4 to 7.5: 1, said b having a drug-extract ratio of 3 to 8: 1. ) And the extract of c) having a drug-extract ratio of 5-7: 1 is about 0.5 to about 5 parts of the extract of a) in the composition, about It is present in a ratio of 2.75 to about 4 parts of the extract of b) and about 2.5 to about 5.5 parts of the extract of c).

  In an even more preferred embodiment of the composition of the present invention, the extract of a) above having a drug-extract ratio of 4 to 7.5: 1, the above having a drug-extract ratio of 3 to 8: 1. an extract of b) and an extract of d) having a drug-extract ratio of 0.5 to 5: 1, wherein about 1 to about 4 parts of the extract of a) above in the composition; Present in a ratio of about 3 to about 4 parts of the extract of b) and about 1 to about 3.5 parts of the extract of d).

  In an additional more preferred embodiment of the composition of the present invention, the extract of said a) having a drug-extract ratio of 4 to 7.5: 1, said drug having a drug-extract ratio of 3 to 8: 1. B) extract, c-7 extract having a drug-extract ratio of 5-7: 1 and d) extract having a drug-extract ratio of 0.5-5: 1. About 0.5 to about 4 parts of the extract of a), about 2.5 to about 3 parts of the extract of b), about 2.5 to about 5.25 in the composition. Part of the extract of c), and about 0.5 to about 3.75 parts of the extract of d).

  In an even more preferred embodiment of the composition of the present invention, the extract of a), the extract of b), the extract of c) and the extract of d) are contained in the composition. About 2.5 parts of the extract of a), about 3 parts of the extract of b), about 2.5 parts of the extract of c) and about 1.5 parts of the d) Present in the ratio of the extract.

  As is apparent from the Examples section, the corresponding composition showed particularly good efficacy.

  In a further preferred embodiment of the composition according to the invention, the composition further comprises olive oil.

  The addition of olive oil to the composition is preferred because it is an excellent carrier and it promotes the solubility of the extract. Olive oil is a fat derived from olives, and various methods for its production have been known in the art for centuries (for example, Olive oil production on bronze age Crete: nutritional properties, processing methods and storage life of Minoan Olive oil. Riley, FR: See Oxford Journal of Archeology, Volume 21, Issue 1, pp. 63-75, February 2002). According to the present invention, virgin olive oil is preferred over pomace oil, ie, chemically extracted olive oil. Preference is also given to olive oil that has been soaked, ie extracted at a temperature preferably not exceeding 27 ° C. Preferably, the olive varieties used for the production of olive oil is Olea europea, which is preferably harvested in a Mediterranean country.

  The ratio of the added olive oil extracts a), b), or a), b) and c), and / or d) in the composition obtained as a result of the addition of olive oil, preferably in mass 1 part olive oil versus 4 parts extract.

  In another preferred embodiment of the invention, the composition of the invention is a pharmaceutical composition.

  The term “pharmaceutical composition” as used herein relates to a composition for administration to a patient, preferably a human patient. Accordingly, the pharmaceutical composition of the present invention consists of a plant extract as defined herein above and optionally olive oil, or it comprises, for example, pharmaceutically acceptable carriers, excipients, diluents and And / or include additional agents, such as additional pharmaceutically effective agents. Examples of suitable pharmaceutical carriers, excipients and / or diluents are well known in the art and include phosphate buffered saline solutions, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions Etc. are included. Compositions containing such carriers can be formulated by well-known and commonly used methods. These pharmaceutical compositions can be administered at a dosage suitable for the subject, such as those outlined herein below.

  The composition can be in solid or preferably liquid form, in particular in the form of a powder (s), a tablet (s), a capsule (s) or a solution (s). it can. For ease of manufacture and administration, a more preferred dosage form is a soft gel capsule comprising a composition of the present invention, preferably a composition of the present invention comprising olive oil.

  Administration of suitable compositions can be accomplished by different methods, preferably by methods other than parenteral, for example, preferably by oral administration. The dosage regimen can be determined by the attending physician and clinical factors. As is well known in the medical arts, the dosage for any one patient is the patient's size, body surface area, age, individual compound to be administered, sex, time and route of administration, general health status As well as many other factors, including other drugs being administered at the same time. The composition can be administered at a dosage of 1 mg to 100 mg / kg body weight per day, which also depends on the selected titer of the plant extract within the composition of the invention; Considering the factors and the selected dilution of the pharmaceutically active substance, ie the plant extract of the composition of the invention, doses below or above this typical range are expected. Progress can be monitored by periodic assessment.

  Formulations for oral administration include, for example, (sterile) aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil, and organic esters such as ethyl oleate. Aqueous carriers include alcoholic / aqueous solutions, emulsions or suspensions, including water, saline and buffered media. Vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Such vehicles include fluid and nutrient replenishers, electrolyte replenishers (eg, Ringer's dextrose-based replenishers), and the like. Preservatives and other additives such as antimicrobial agents, antioxidants, chelating agents, inert gases and the like may also be present. Said pharmaceutical composition is also expected to comprise further pharmaceutically active agents known in the art to be effective in the treatment of the illnesses referred to herein, for example in the treatment of illnesses or diseases associated therewith. . Conventional excipients include binders, bulking agents, lubricants and wetting agents. Preferably, the composition of the invention is administered orally in the form of a soft gelatin capsule suitable for dissolving in the intestine (and releasing the composition of the invention). In the art, this dosage form is known to allow rapid absorption of ingested compounds. In this case, it is preferred to utilize the composition comprising the added olive oil described hereinabove with or without additional agents as defined herein. However, the addition of other vegetable oils such as flax seed oil or black cumin seed oil or additional vegetable oils is also envisaged.

  In another aspect of the invention, the pharmaceutical composition of the invention is for use in opioid abuse, opioid dependence, alcohol abuse and / or alcohol dependence treatment and / or for opioid and / or alcohol withdrawal. For use in the treatment of symptoms.

  Alcohol abuse and alcohol dependence are well-known illnesses in the art that describe the repeated use of alcoholic beverages despite poor results. Accordingly, there are various classification systems that can diagnose a person as suffering from alcohol dependence and alcohol abuse. In accordance with the present invention, all of the above classification systems can be used for diagnosing a patient as being appropriate for treatment as described herein. Specifically, classification according to the Guide to Diagnosis and Statistics of Mental Disorders (DSM) or the World Health Organization can be used. According to the latest edition (DSM-IV), the criteria for alcohol dependence include: tolerance; withdrawal symptoms or clinically defined alcohol withdrawal syndrome; use higher or longer than intended Sustained desire or unsuccessful efforts to reduce the use of alcohol; time is spent to obtain alcohol or to recover from the effects of alcohol consumption; social, professional and recreational pursuits Have been abandoned or reduced due to the use of alcohol; and continues to be used despite knowledge of the harm (physical or physiological) associated with alcohol. At least three criteria must appear in a 12 month period. For example, a so-called alcohol use disorder identification test (AUDIT; see Babor et al., AUDIT, The Alcohol Use Disorders Identification Test, Guidelines for Use in Primary Care, 2nd edition, World Health Organization Mental Health and Substance Dependent) It can be used as a screening tool to identify abuse of sexual alcohol. A test that is more specifically directed to the diagnosis of alcohol dependence is the alcohol dependence severity questionnaire (SAD-Q). Alcohol dependence is distinguished from alcohol abuse by the presence of symptoms such as tolerance and withdrawal symptoms. Alcohol abuse can lead to alcohol dependence. At present, and with regard to the next issue of DSM (DSM-V), it is expected to combine alcohol abuse and alcohol dependence into one integrated disorder, namely alcohol use disorder (AUD), which includes alcohol A moderate to severe graded clinical severity that accounts for the difference between abuse and dependence of the disease will be included. In accordance with the above classification, the present invention also relates to the treatment of diseases including alcohol abuse and alcohol dependent diseases as noted above.

  Opioid abuse and opioid dependence are equally well known in the art. Again, DSM-IV defines standards for substance dependence and substance abuse. Once a complete patient assessment has been performed, a formal diagnosis of either opioid dependence or abuse should be made. Diagnosis of substance dependence or abuse in accordance with the latest DSM-IV diagnostic scheme is based on a cluster of behavioral and physiological effects occurring within a specific time frame. The diagnosis of dependence is always performed before the diagnosis of abuse. For example, the diagnosis of abuse is performed only when the criteria of DSM-IV for dependence have never been satisfied.

  Dependence is defined as at least three occurrences of the following criteria within a 12 month period: tolerance (significant increase in amount; significant decrease in action); characteristic withdrawal symptoms; to alleviate withdrawal symptoms Substance is ingested; ingested in a larger amount than intended and for long periods of time; persistent desire to stop or repeated failed attempts; obtain, use, much to recover Time / activity; important social, professional, or recreational activities have been abandoned or reduced; and adverse consequences (eg failure to fulfill role obligations, use when physically hazardous) Continued use despite knowledge of

  Abuse is defined as the occurrence of at least one of the following criteria within a 12-month period (the criteria must never meet the criteria for substance dependence for the class of substance being judged): Repeated use that results in failure to meet the main role obligations at home or school; Repeated use in physically dangerous situations; Legal issues related to repeatable substances; and caused by substances Or continued use despite worsened or recurrent social or interpersonal problems.

  In the use of the DSM-IV criteria, clinicians have shown that substance dependence is associated with physiological dependence (ie, there is evidence of tolerance or withdrawal symptoms) or is not associated with physiological dependence (ie, tolerance or withdrawal symptoms). Should be identified. In addition, patients can be categorized differently if they are currently manifesting a pattern of abuse or dependence, or are in remission. Patients in remission are divided into four subtypes based on whether abuse or dependence criteria are met and over what time frame: complete, early partial, persistent, and persistent partial Can be divided into The remission category can also be used for patients receiving agonist therapy (eg, methadone maintenance) or for patients living in a controlled drug-free environment.

  The term “opioid” is known in the art to refer to a psychotropic chemical that targets, for example, binds to an opioid receptor and is therefore used in connection with the present invention. These psychotropic chemicals are not limited to natural alkaloids, such as those found in poppy resins, for example, which are called “opiates”. In other words, a chemical that can be included under the term “opioid” includes a chemical that can be included under the term “opiate”. Opioids include, for example, i) natural opiates (eg morphine, codeine, thebaine, oripavine or salvinorin A), ii) esters of morphine neopiates (eg diacetylmorphine (heroin)), nicomorphine, dipropanoylmorphine, Desomorphine, acetylpropionylmorphine, dibenzoylmorphine or diacetyldihydromorphine); iii) semi-synthetic opioids made from either natural opiates or morphine esters (eg hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine or buprenorphine); iv) synthetic opioids (eg fentanyl, pethidine, levorphanol, methadone, tramadol or dextropropo Shifen); and v) the endogenous opioids (e.g. endorphins, enkephalins, dynorphin compounds can be classified into morphine and Endomorphin acids). Thus, the term “opioid” can be replaced by any of the above-referenced classes of substance (s) belonging to the above term. Thus, abuse behavior involving the class of the substance (s) in the subject and the symptoms that occur during the latter withdrawal can now be successfully treated.

  According to the present invention, “treatment of symptoms” of alcohol and / or opioid withdrawal is meant to refer to an improvement or attenuation, preferably elimination, of symptoms associated with alcohol and / or opioid withdrawal. Because most of the symptoms themselves can be classified as medical illnesses or diseases, the term “treatment” for symptoms is used. Accordingly, the present invention also relates to a pharmaceutical composition of the present invention for use in the treatment of opioid and / or alcohol withdrawal.

  Symptoms of alcohol withdrawal are known in the art and are triggered upon reduction or cessation of alcohol consumption after prolonged excessive alcohol consumption. Withdrawal symptoms are mainly due to hyperexcitability of the central nervous system (CNS hyperexcitability; (Saitz et al., JAMA., 272 (7): 519-23 (1994)). Degrees vary from mild symptoms such as mild sleep disturbances and mild anxiety to very severe and life-threatening, including mental confusion, especially hallucinations and convulsions (which can result in death) in severe cases These symptoms are characteristic of arousal due to a decrease in blood alcohol levels during sleep, and the severity of alcohol withdrawal depends on age, genetics, and most importantly alcohol It depends on a variety of factors, including the degree of intake and the length of time the person has used alcohol and the number of previous detoxifications, such as agitation, alcoholic hallucinations, anorexia, anxiety, panic Work, tension disease, confusion, tremor delirium, divorce, depression, loss of reality, sweating, diarrhea, euphoria, fear, gastrointestinal upset, headache, high blood pressure, hyperthermia, insomnia, irritation, migraine, Nausea and vomiting, palpitations, psychosis, rebound REM sleep, restlessness, seizures and death, sweating, hyperhidrosis, tremors, and / or weakness These symptoms can cause alcohol-dependent illness Occurs when the affected subject is prevented from taking alcohol.

  Symptoms of opioid withdrawal are known in the art (see, eg, Dansou et al., Rev Prat., 62 (6): 837-41 (2012)). Physical symptoms include, for example, tremors, convulsions, muscle and bone pain, chills, sweating, persistent erections, tachycardia, pruritus, restless legs syndrome, flu-like symptoms, rhinitis, absence, sneezing, vomiting, diarrhea, weakness and Psychological symptoms may include, for example, physical discomfort, malaise, desire, anxiety, panic attacks, delusions, insomnia, dizziness, nausea, and / or depression.

  These symptoms occur when a subject with an opioid-dependent disease is prevented from administering opioids to him or herself.

  In a preferred embodiment of the composition for use according to the present invention, said composition should be administered at a dose of about 18.5 to about 77.5 mg / kg per day.

  In this embodiment, the dose to be administered is determined in a manner that is particularly acceptable to both clinicians and patients, particularly as defined with respect to preferred embodiments of the compositions of the invention, i.e. embodiments that provide specific extract ratios. It has been shown to produce the desired treatment effects. Accordingly, dosages of about 20-75 mg / kg per day, such as 25-70, 30-70, 35-70, 40-65, 45-60 or 50-60 mg / kg per day are also anticipated. More preferred is a dose of about 50, 55, 60 or 65 mg / kg per day (for each value), most preferably 50 mg / kg per day.

  As mentioned herein above, the dose of the drug is generally adjusted by the attending physician depending on various factors. Thus, depending on, for example, the chosen concentration of the extract of the composition at the time of administration, the daily 77.5 mg / kg range referred to above is greater than 2.5 mg, eg 5 mg, 7.5, 10 , 15, 20, 25 mg (for each value) or greater than 50 mg, larger amounts of the composition of the invention can be administered. As a guide for administration, the total daily dose should not exceed 60 mg of composition with an average drug extract ratio of 5: 1 and containing about 20% of inactive additive.

  According to the present invention, the extract of said a) having a drug-extract ratio of 4 to 7.5: 1, the extract of said b) having a drug-extract ratio of 3 to 8: 1, An extract of said c) having a drug-extract ratio of 5-7: 1 and an extract of said d) having a drug-extract ratio of 0.5-5: 1 are present in the composition. 0.5 to about 4, preferably about 2.5 parts of the extract of a), about 2.5 to about 3, preferably about 3 parts of the extract of b), about 2.5 to about The present invention comprises about 5.25, preferably about 2.5 parts of said extract of c), and about 0.5 to about 3.75 parts of said extract d) Of the composition is administered at a dose of 20-70, more preferably 20-60, even more preferably 20-40, most preferably 25-30 mg / kg per day. Doses of 10-20 mg / kg per day, 10-15 mg / kg per day and 15-20 mg / kg per day are also envisaged.

  For example, 600 mg (300 mg of Raphanus extract (preferably having a drug-extract ratio of 3: 1), 180 mg of Theobroma extract (preferably having a drug-extract ratio of 5: 1), Preferred books of 60 mg Passiflora extract (preferably having a 5: 1 drug-extract ratio) and 60 mg Crocus extract (preferably having a 4: 1 drug-extract ratio) The composition of the invention can be administered three times a day, preferably after a meal, alone or in combination with any of the additives described herein, preferably 4 daily administrations of the latter dose. Continue for ~ 6 weeks.

  In a more preferred embodiment of the composition for use according to the invention, said dose should be administered for at least 2 weeks.

  In this embodiment, the treatment period as defined in particular with respect to the preferred embodiment of the composition of the invention, i.e. the embodiment providing a specific extract ratio, is the desired treatment, in particular in a manner acceptable to both the clinician and the patient. It has been shown to produce the effects of However, treatment periods of at least 7, 8, 9, 10, 11, 12, 13 days or at least 17 days, 3 weeks, 4 weeks or at least 5 weeks or longer (for each value) are also envisaged. Presumably, as mentioned above in the present invention, the dose of drug as well as the duration of treatment is generally adjusted by the attending physician depending on various factors. Thus, depending on, for example, the selected concentration of the extract in the composition when administered, a longer treatment period, for example when using lower extract concentrations, is sensible and efficient to achieve the desired treatment effect. Strategy. Also, the duration of treatment can vary based on perceived dependence on alcohol and / or opioids or their level of abuse: in general, the lower the perceived level, the shorter the duration of administration. In most cases of opioid and / or alcohol abuse or dependence, administration of a composition as defined herein above for at least 2 to 4 weeks, particularly at the doses referred to above, is sufficient for treatment. . Preferably, alcohol abuse or dependence is treated by administration of the composition of the invention for at least about 20 days, more preferably at least 25, for example 30 days.

  According to the invention, the extract of a) preferably having a drug-extract ratio of 4 to 7.5: 1, the extraction of b) having a drug-extract ratio of 3 to 8: 1 The extract of c) having a drug-extract ratio of 5-7: 1 and the extract of d) having a drug-extract ratio of 0.5-5: 1 in the composition. About 0.5 to about 4, preferably about 2.5 parts of the extract of a), about 2.5 to about 3, preferably about 3 parts of the extract of b), about 2.5 From about 5.25, preferably about 2.5 parts of the extract of c), and about 0.5 to about 3.75 parts of the extract of d), In compositions of the invention administered at a dose of 20-70, more preferably 20-60, even more preferably 20-40, most preferably 25-30 mg / kg per day. And, the administration of (for each value) of at least 7, 8, 9, 10, 11, 12, 13, 14 days or at least 17 days, 3 weeks, maintained for 4 weeks or at least 5 weeks.

  In another aspect, the present invention relates to a method for producing a composition comprising an extract of a plant belonging to the genus Raphanus and an extract of a plant belonging to the genus Theobroma, comprising the following steps: a) Extracting at least aerial roots, seeds and / or bulbs of a Raphanus plant with hydrophilic, medium polarity and / or lipophilic solvent; b) at least a fruit of the Theobroma plant with hydrophilic and / or medium And c) combining the extract of step a) with the extract of step b), thereby comprising an extract of a plant belonging to the genus Raphanus and an extract of a plant belonging to the genus Theobroma The above composition is produced.

  The definitions, combinations and specific parameters relating to extraction referred to herein above apply mutatis mutandis to this embodiment and its preferred modifications referred to herein below.

  In a preferred embodiment of the method of the invention, the method comprises the following further steps: d) extracting at least the flowers of a plant belonging to the genus Passiflora with a hydrophilic, moderately polar and / or lipophilic solvent; and And / or e) extracting at least the flowers of a plant belonging to the genus Crocus with a hydrophilic, moderately polar and / or lipophilic solvent; prior to step c) (in which case the extract of step d) and The extract of step e) is combined with the extract of steps a) and b) above), or after step c) (in that case the extract of step d) and / or the extraction of step e) In a further step f) in combination with the composition of step c), whereby an extract of a Raphanus plant, an extract of a Theobroma plant, a Passiflora plant Producing distillate and / or Crocus spp composition comprising plant extracts of.

  As mentioned hereinabove, in a further preferred embodiment of the composition of the invention, the composition for use of the invention or the method of the invention, the plant belonging to the genus Raphanus is a Raphanus satius plant And / or a plant belonging to the genus Theobroma is a Theobroma cacao plant.

  A single extract as well as combinations thereof, such as a single extract forming a composition of the invention as described herein above, and combinations thereof, preferably in a sealed container, preferably 4 Stored at a temperature of ~ 8 ° C and protected from sunlight either by storage in the dark or in a container that blocks light from entering the container. Preferably, the container is hermetically and oxygen-free. The extract combination is preferably carried out in the dry state of the respective extract. The minimum shelf life is expected to be 2 years for fluid (eg alcoholic) extracts and at least 3 years for dry extracts.

  In an additional preferred embodiment of the composition of the invention, the composition for use of the invention or the method of the invention as mentioned above, the plant belonging to the genus Passiflora is a Passiflora incarnata plant; and / or Alternatively, a plant belonging to the genus Crocus is a Crocus satius plant.

  Plants from Raphanus satius, Theobroma cacao, Passiflora incarnata and Crocus satius species can then obtain extracts that form the compositions of the invention, the extracts of which are exemplified herein below. Particularly preferred plants that have been used in the composition.

  In this specification, particularly with respect to the aspects characterized in the claims, each aspect referred to in a dependent claim refers to each aspect of each claim (independent or dependent) on which said dependent claim is dependent. It is intended to be combined. For example, independent claim 1 listing three alternatives A, B and C, dependent claim 2 listing three alternatives D, E and F and three alternatives G dependent on claims 1 and 2; In the case of claim 3 listing H and I, the specification is A, D, G; A, D, H; A, D, I; A, E, G; A, E, unless specifically stated otherwise. A, F, G; A, F, H; A, F, I; B, D, G; B, D, H; B, D, I; B, E, G B, E, H; B, E, I; B, F, G; B, F, H; B, F, I; C, D, G; C, D, H; C, D, I; C , E, G; C, E, H; C, E, I; C, F, G; C, F, H; expressly disclosed embodiments corresponding to combinations of C, F, I; It should be.

  Similarly, and where independent and / or dependent claims do not enumerate alternatives, if a dependent claim refers back to multiple preceding claims, the subject matter covered thereby It is understood that every combination is considered explicitly disclosed. For example, in the case of the independent claim 1, the dependent claim 2 referenced back to claim 1, and the dependent claim 3 referenced back to both claims 2 and 1, the combination of claims 3 and 1 is: It will be clearly and explicitly disclosed as being a combination of the subject matter of claims 3, 2 and 1. Where there is a further dependent claim 4 that refers to any one of claims 1 to 3, claim 4 and 1, claim 4, 2 and 1, claim 4, 3 and 1, and claim Combinations of the subject matter of paragraphs 4, 3, 2, and 1 will be disclosed clearly and explicitly.

  The above discussion applies mutatis mutandis to all appended claims.

The figure shows the following:
Figure 1:
Dose-response effect on intraperitoneal administration of morphine or heroin of orally administered extract composition to re-establish motor behavior in rats. Each data point represents the mean (± SD) of 5 rats. ^* Significant difference between baseline and each treatment p <0.001; † Significant difference between that dose vs its lower dose (p <0.001).

Figure 2:
% Reduction in dependence on morphine or heroin after oral administration of the extract composition. Each data point represents the mean (± SD) of 5 rats. ^* Significant difference between baseline and each treatment p <0.001; † Significant difference between that dose vs its lower dose (p <0.001).

Figure 3:
HIC score for mice exposed to ethanol for 72 hours. Mice were treated with different doses of extract or vehicle at 1 and 4 hours and HIC scores were recorded over a 64 hour time course. HIC scores were significantly lower in the groups treated with 40 or 60 mg / kg extract for the first 12 hours (p <0.001).

Figure 4:
Short spindle spindle episode (BSE) activity was recorded in mice after chronic exposure to ethanol. Mice treated with 40 and 60 mg / kg extract composition have significantly less BSE than mice treated with vehicle from 2 to 72 hours after ethanol withdrawal. BSE activity for mice treated with 40 or 60 mg / kg extract composition was significantly lower than mice treated with vehicle (p <0.001).

The examples illustrate the invention:
Example 1 : Self-administration model 1.1 Materials and methods 1.1.1 Extract composition The extract composition used in Example 1 and all other examples was composed as follows:
-2.5 parts Rafanus satius extract, said extract is obtained by extraction as follows:
• Add 500 ml of 30% methanol / water mixture to 90 g of dried and powdered radish in a glass beaker • Heat the solution to 40-50 ° C. for 30 minutes • Filter the solution and evaporate the filtrate under vacuum to dryness Solidify the lyophilized residue for 24 hours (the amount of natural extract obtained was 36.3 g of dry extract)
Add 40% excipient (37 parts maltodextrin and 3 parts silica) so that the extract is standardized for standardization purposes to contain at least 1.5% total flavonoids -3 parts theobroma cacao extract, said extract is obtained by extraction as follows:
Add 1 liter of purified water to 200 g of dried and powdered cocoa fruit in a glass beaker Heat the solution at 70-80 ° C. for 45 minutes.

Filter the solution and evaporate the filtrate to a volume of 100 mL. Freeze and lyophilize for 24 hours.

    Add excipients and standardize the extract to contain a minimum concentration of procyanidins.

-2.5 parts of Passiflora incarnata extract, said extract being obtained by extraction as follows:
Add 750 mL of methanol to 175 g of dried and powdered passion flour in a glass beaker. Heat the solution at 40-50 ° C. for 30 minutes.

    • Filter the solution and evaporate to dryness.

    Freeze the residue for 24 hours.

    Add excipients and standardize the extract to contain minimal concentrations of flavonoids.

-1.5 parts of Crocus satius extract, said extract being obtained by extraction as follows:
Add 300 mL of ethanol to 10 g of dried and powdered saffron flowers in a glass beaker Heat the solution at 30-45 ° C. for 30 minutes.

    • Filter the solution and evaporate to dryness.

    Freeze the residue for 24 hours.

    Add excipients and standardize the extract to contain the minimum concentration of safranal.

  -Mix the dried extract in a mixture of water and olive oil.

1.1.2 Intravenous self-administration device The response in either of the two levers (placed 15 cm apart on the front wall of the cage of each operant test) is compatible with an IBM with the Med Associates interface. Recorded on a computer with The intravenous self-administration system was designed by Weeks (1972) (Weeks JR. Long-term intravenous infusion. In: Myers RD, Editor. Methods in Psychobiology. Vol. 2. Academic Press; New York: 1972. pp. 155- 168), composed of a polyethylene silicon cannula, Intech harness and swivel, and Harvard Apparatus infusion pump. The formation of a stick-pushing reaction was accomplished by first training the rat to push the stick for water. The cannula was then implanted into the external jugular vein according to the procedure described by Weeks (1972) (see above). The self-administration study began with a 16-hour night session followed by a 1-hour session per day for 6 days per week. The lever pushing reaction resulted in an injection of 10 ml of drug solution (0.01 mg of morphine sulfate) in about 0.2 seconds or 50 ml of drug solution.

1.1.3 Crossroad Maze Procedure The device was made of black Plexiglas and consisted of two runways intersecting at a right angle in the middle. Each maze arm was 40 × 10 cm (length × width) in size. Two of the arms opposite each other had walls measuring 40 cm in height (closed arms), while the other two arms had no walls (closed arms). The maze was raised 52 cm above the floor. It was placed in a dark room so that only the open arms were bright and each had its own 40 W incandescent lamp. Place the animal in the middle of its maze and count the number of intrusions into each type of arm (defining that all four paws are in the arm is intruded) and are spent on each type of arm. The time was also counted. The test was terminated 5 minutes after the animal was centered. The following scales were calculated: total number of arm intrusions, open and closed arm intrusions, time in open and closed arms, and percentage of total time spent in open arms. Changes in the total number of arm intrusions reflect general activity indicators, while changes in the percent scale constitute anxiety indicators. An increase in the percentage of open arm time reflects an anxiolytic state, while a decrease in the percentage of open arm time reflects an anxious state. Animal movements were recorded by using an overhead video camera and VCR. They were subsequently scored by “blind” observers.

1.1.4 Microdialysis test Under pentobarbital anesthesia (50 mg / kg ip), the rats were placed with a microdialysis guide cannula (CMA: 8309010; Acton, Mass.) Over the nucleus accumbens and bilateral injector guides on the legs. It was stereotactically embedded 0.5 mm above the interstitial nucleus (Paxinos and Watson, 1986, The rat brain in stereotaxic coordinates, 2nd edition. (Academic Press, London)). The animals were monitored for proper recovery but were otherwise undisturbed for 4 days after surgery. In the afternoon prior to the in vivo microdialysis experiment, the rats were placed in a cubic microdialysis chamber for free access to food and water. Rats were briefly anesthetized with Brevital (45 mg / kg ip) and a dialysis probe was inserted through the guide cannula. Artificial cerebrospinal fluid containing 146 mM NaCl, 2.7 mM KCl, 1.2 mM CaCl ₂ , and 1.0 mM MgCl ₂ was continuously delivered by a Harvard syringe pump at a flow rate of 1 ml / min. Perfusate collection began the next day. Twenty fractions were collected in vials containing 2.0 ml of 1.1 M perchloric acid solution (containing 50 mg / l EDTA and 50 mg / l sodium metabisulfite). Two hours after baseline collection, 18-MC (10 mg) or vehicle was administered topically into the interlegal nucleus and the rats were given a dose of morphine (5 mg / kg ip) or saline. Dialysate sample collection was then continued for 3 hours. When the experiment was completed, the rats were killed by pentobarbital overdose. Each brain was removed, frozen and sliced in a cryostat. Traces left behind by the probe were identified and their exact location determined by reference to the Paxinos and Watson illustration (1986) (The rat brain in stereotaxic coordinates, 2nd edition. (Academic Press, London)) .

  Dialysate samples were assayed using electrochemical detection by high pressure fluid chromatography (HPLC) for dopamine, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). The HPLC system consisted of an ESA autosampler, ESA solvent delivery system, C18 column. The mobile phase consisted of 10% HPLC-guided 0.075 mM sodium dihydrogen phosphate monohydrate, 0.0017 mM octane sulfonic acid, and 25 mM EDTA adjusted to pH 3.0 with phosphoric acid. . The flow rate was set at 0.53 ml / min.

1.1.5 Microinjection test Rats were placed under anesthesia with pentobarbital sodium anesthesia (50 mg / kg) with bilateral instrument injector guides (Plastics One, Roanoke, VA) 0.5 mm above the interlegal nucleus (Paxinos and Watson, 1986, see above). Obturators were screwed into the injector guide. The injector guide was fixed to the skull using stainless steel screws and skull-forming cement. Rats were returned to individual cages and provided food and water ad libitum. The cage was left on the heating pad overnight and the next day the rats were returned to the colony room. Rats were utilized in a microinjection study after recovering from surgery for at least 4-5 days. Morphine and extract composition (or vehicle) are administered topically into the interlegal nucleus using an infusion pump (Harvar Apparatus); all such treatments during the 1 minute infusion to prevent reflux through the guide cannula The injection cannula was kept in place for an additional minute after the treatment was given.

1.2 Results The extract composition reduced morphine abuse self-administration; at 40 mg / kg, these effects generally lasted 18-64 hours. The extract mixture (40 mg / kg) appears to provide a downward shift in the entire unit-injection dose-response curve of the self-administered drug without any left or right displacement, which reduces the enhancement efficacy (ie , Other abused drugs such as morphine and nicotine were less potent in the presence of the extract composition). It should also be noted that the extract mixture was powerful in reducing self-administration. The extract mixture showed very good activity against the opium receptor.

Example 2 : Motor Behavior Test 2.1 Materials and Methods Rats weighing 250 g ± 10% were utilized in the experiment. Each group consisted of 5 animals.

  The rotor rod performance test is a test used herein to evaluate the motor coordination of rats after induction of dependence on morphine or heroin. 0.04 mg / kg morphine, .0, following an infusion of 10 ml drug solution (0.01 mg morphine sulfate) or 50 ml drug solution (0.015 mg heroin sulfate) of the same concentration in about 0.2 seconds. Rats respond after administration of 04 mg / kg heroin.

  To assess the effect of the experimental treatment, the experiment was performed as the dose rate baseline stabilized within a 10% variation from one day to the next 5 days. This required 20 days of testing to demonstrate consistent motor performance using dependency and rotor rod performance tests. Rats were given daily intraperitoneal doses of morphine or heroin to equilibrate behavior. After oral administration of the extract, the dose of morphine or heroin was adjusted to equilibrate motor coordination similar to the “normal” state.

  The performance measure of motor behavior was performed using a commercially designed and constructed accelerating rotor rod (Rotamex). It was quantified as the animal's ability to stay in place on the rotating rod to accelerate motor coordination. Prior to drug administration, the rats were gradually trained to remain on the rod by giving them 6-8 exercise sessions of 3 minutes per day. The rats were trained for a period of 3 minutes with increasing rod speeds of 3, 6, 9, 12, and 15 rpm. An electric shock (2 mA, AC) was present on the floor of the device to motivate the animal to remain on the rod. The time when the animal fell was automatically recorded by photocell detection. An individual animal was considered trained when it reached the criteria that it stayed on the rod for a full 3 minute session in two consecutive tests at 15 rpm. Only rats that met this criterion after 2 days of training were used in these experiments. All tests were performed at least 2 hours after the last training test. Drug was given 30 minutes before the test session by intraperitoneal injection. The animal was placed on the rod while rotating it at 10 rpm. Once placed, the rotational speed of the rod was increased at a rate of 8.3 rpm / min. The total possible test session duration was 3 minutes. The time of fall and the number of rotations per minute at the time of fall were recorded for each animal.

  All data are shown as mean ± standard deviation (SS) as either mg / Kg or% and use one-way analysis of variance followed by post-hoc test (Tukey's test) (95% confidence) for multiple comparisons (SPSS version 17). P values less than 0.05 (<0.05) were considered statistically significant.

2.2 Results and Conclusions Increasing doses of extract composition administration significantly (p <0.001) reduced morphine and heroin doses to stabilize motor coordination in rats following the rotarod performance test. (FIG. 1). This latter effect was dose dependent and the percentage of morphine or heroin reduction was significantly reduced by higher doses (Figure 2). The 50% dependence reduction values were 9.8 and 12.5 mg / kg for heroin and morphine, respectively (Figure 2). The results show that the extract reduced morphine and heroin dependence in a dose-dependent manner, but did not show the superiority of either opioid narcotic used.

Example 3 : Hyperexcitability of the CNS associated with alcohol withdrawal in an ethanol-dependent mouse model 3.1 Materials and methods Animals Adult male mice (80-90 days of age) were used in these experiments. The mouse body weight was 25-30 g at the start of the experiment.

Extract Preparation and Administration The extract composition was dissolved in saline and saline alone was used as the vehicle. The extract composition was administered orally.

Ethanol exposure and measurements Mice were chronically exposed to ethanol vapor in a Plexiglas inhalation chamber (60 × 36 × 60 cm ³ ). Briefly, ethanol (95%) was volatilized by passing air through an airstone submerged in ethanol. The ethanol vapor was mixed with fresh air and delivered to the chamber at a rate of 10 l / min, which maintained the ethanol concentration in the chamber in the range of 10-13 mg / L air. Before entering the ethanol chamber, intoxication was initiated by the administration of ethanol (1.6 g / kg; 8% w / v; ip.), And the blood ethanol concentration (BEC) was adjusted to pyrazole (1 mmol), an alcohol dehydrogenase inhibitor. / Kg) administration. Mice maintained in a control (air) chamber were given saline and pyrazole injections. The accommodation conditions in the inhalation chamber were the same as the accommodation conditions in the colony room. A blood sample was taken for BEC determination immediately after removal of the mouse from the inhalation chamber. The chamber ethanol concentration was determined daily by taking an air sample (2 ml) with an airtight syringe through a port in the chamber wall. The sample was then transferred to a Venoject ™ tube for later analysis using an enzymatic spectrophotometric assay procedure. The ethanol concentration in the chamber is expressed as mg / L air. Blood samples were collected from the retroorbital sinus using heparinized capillaries. The sample was centrifuged for phase separation and 5 μl of plasma was injected into an Analox Instrument analyzer (Lunenburg, Mass.). BEC (in mg / dl) was recorded by measuring the oxygen uptake caused by the oxidation of ethanol to acetaldehyde and hydrogen peroxide by ethanol oxidase.

Handling-induced convulsions (HIC)
Mice were randomly assigned to ethanol treatment conditions and then divided into several groups (control and concentration dependent groups). Mice were continuously exposed to ethanol vapor for 72 hours in the inhalation chamber. A blood sample was taken to determine the blood ethanol concentration (BEC) upon removal from the inhalation chamber. At 1 and 4 hours after ethanol withdrawal, mice were given an oral dose of extract composition (0, 20, 40 or 60 mg / kg). Convulsions induced after withdrawal of alcohol were recorded as handling-induced convulsions (HIC) responses. The HIC response has proven to be a sensitive and reliable indicator of CNS hyperexcitability associated with ethanol withdrawal.

Electroencephalographic activity A separate group of mice was used to evaluate the electrocardiographic scale for ethanol withdrawal. Mice were implanted stereotaxically with long-term indwelling electrodes as previously described. Briefly, a unipolar stainless steel semi-micro electrode (120 mm) is connected to the hippocampus (AP: −1.65 mm; L: 1.5 mm; V: −2.25 mm), amygdala (AP: −0.7 mm; L: -2.25 mm; V: -5.25 mm), and nasal area (AP: +4.0 mm) for use as a reference electrode in the visual cortex (AP: -3.0 mm; L: -2.0 mm) Embedded in stainless steel screws in L: +0.5 mm). Coordinates were obtained compared to Bregma. The electrode was connected to a 4-pin MicroTech plug and secured to the skull using a dental acrylic and photocuring resin composite. Three to five days after surgery, baseline electroencephalogram (EEG) activity was recorded every 2 hours over a period of 8 hours from freely moving mice. The next day, mice were placed in the inhalation chamber and given 72 hours of continuous exposure to ethanol vapor. Mice were given the extract composition (0, 40 or 60 mg / kg) orally at 1 and 4 hours after ethanol withdrawal. EEG data was collected during withdrawal and additional samples were recorded at 24, 32, 48, and 72 hours after withdrawal. The recording session was conducted in an electrically shielded chamber and the electrode cable was connected to a Grass amplifier. Spontaneous EEG data was digitized by a CED analog-to-digital converter, and a series of high-voltage EEG activities known as short-time spindle-shaped episodes (BSE) were identified by a computer program (Spike 2). Briefly, automated analysis involved identifying and classifying bursts of EEG activity at frequencies of 7 and 9 Hz and a period of at least 1 second. Data were presented as percent BSE activity (ie, the cumulative duration of all BSE events compared to the entire duration of each recording session).

Data analysis Data were presented as HIC scores or BSE activity, and data between groups were analyzed by analysis of variance (ANOVA) followed by a post-hoc test. P <0.05 was considered significant.

3.2 Results The extract composition was administered at 1 and 4 hours after ethanol withdrawal. Extracts at doses of 40 and 60 mg / kg significantly (p <0.001) reduced HIC scores compared to mice treated with vehicle (FIG. 3). This reduction was observed during the first 12 hours after withdrawal. The extract dose of 20 mg / kg showed a pattern of reduction in the HIC score; however, they were not significant. Furthermore, there was no difference in HIC score between the 40 and 60 mg / kg treatment groups (FIG. 3). Similarly, 40 or 60 mg / kg extract composition significantly reduced BSE activity in a time-dependent manner (FIG. 4). Maximum reduction in BSE activity was observed during the first 36 hours after alcohol withdrawal. However, after 36 hours, BSE activity began to decline in the vehicle-treated group. Finally, treatment with repeated withdrawal symptom extract compositions was effective in blocking the onset of withdrawal sensitization observed in mice treated with vehicle.

Example 4 : Treatment of alcohol dependence in a patient with a depressive disorder The extract composition has a serotonin reuptake inhibitor. Therefore, alcohol-dependent patients with complicated major depressive disorder were compared.

4.1 Method Four alcohol dependent patients with major depressive disorder in a municipal alcohol clinic were given the extract composition (40 mg / kg) in a small pilot study. During the 6 week study period, patients continued their routine treatment in the clinic. Prohibition was not required but recommended. The patient went to the hospital weekly for the first 2 weeks, then at 4 and 6 weeks. Outcome measures were the alcohol use disorder specific test (AUDIT), relentless and compulsive drinking scale (OCDS) and drinking diaries.

4.2 Study Participants Three men and one woman aged 31-47 years who were voluntarily seeking outpatient treatment for alcohol issues at two alcoholic clinics in Jordan. History of at least 5 years of severe drinking (average 4 or more daily drinks for men and 3 or more daily drinks for women), serious depression as defined by Beck Depression Survey Table II (BDI-II> 16) who were interested in participating in the study voluntarily were encouraged to be screened by the study physician by their clinician. The patient was interrogated by applying the Structured by a study physician (psychologist LM). The time since the last previous hospitalization detoxification had to be at least 4 weeks. In addition, the eligible patient had to be in a depression episode that lasted longer than 2 weeks. Exclusion criteria include use of other substances screened by urinalysis (amphetamines, benzodiazepines, cocaine, tetrahydrocannabinol and opiates), schizophrenia or other mental disorders, and bipolar I and II disorders Included serious risk of suicide, pregnancy or breastfeeding, severe untreated physical problems, or severe liver dysfunction and mental disorders. Other medications prescribed by the participant's physician were allowed, except for other antidepressants. All patients were Jordanians. The current average length of depression was 22 months. Informed consent was obtained from all patients participating in the study.

4.3 Study design Four patients were screened first. A screening interview (SCID) was performed to confirm the diagnosis of MDD and alcohol dependence. Patients are relentless and compulsive drinking scale (OCDS; Anton RF: Obsessive compulsive aspects of craving: development of the Obsessive Compulsive Drinking Scale, Addiction 2000, 95: (211-217)) and alcohol use disorder specific test (AUDIT; Saunders JB et al., 1993, Development of the alcohol Use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumtion II, Addition 1993, 88 (6): 791-804) AUDIT-QF (Aalto M et al., 2006, Alcohol Clin Exp. Res., Effectiveness of structured questionnaires for screening heavy drinking in middle aged women, 30 (11): 1884-1888), and AUDIT-3 ( Gual A et al., 2002, Alcohol (37 (6): 591-596, Audit-3 and Audit-4: effectiveness of two short forms of the alcohol) were used for detailed alcohol analysis. Record consumption during a 6 week treatment period for a specific test Was conducted using a personal drinking diary for all days.

  Eligible patients were given 40 mg / day of the extract composition orally. Patients were instructed to take the study drug in the morning. The patient was allowed to call the investigator at any time. If the patient did not appear on the scheduled visit, a new appointment was proposed.

  During the 6 week treatment period, patients returned to the study site for data collection and drug check and distribution at 2, 4 ± 2, and 6 ± 2 weeks. At each visit, the drinking diary and study drug intake since the previous visit were recorded from the pharmacotherapy diary. Study medication was ensured by counting pills from returned used bottles. Results were recorded in specific weeks: OCDS (weeks 0, 2, 4 and 6); AUDIT (weeks 0, 2 and 6). Clinical laboratory tests (MCV, AST, ALT, CDT, and GGT) were performed at the start of the study and repeated at 2, 4, and 6 weeks to ensure the safety of drug therapy. If the breath or blood test for alcohol was not performed but the patient was clearly drunk, a new appointment was suggested.

Statistical analysis Statistical analysis of all primary and secondary results was performed by independent sources.

4.4 Results Baseline AUDIT and alcohol use history are similar in AUDIT scores that decreased from baseline from 27.6 ± 6.3 to 12.47 ± 7.9 in the extract composition group (40 mg / kg) doing. The overall reduction was highly significant (p <0.0001).

  Alcohol consumption as measured by AUDIT QF (quantity-frequency) score was significantly reduced: extract composition (40 mg / kg) from 6.1 ± 1.4 to 3.7 ± 2.3, and 6. Reduced from 0 ± 1.5 to 4.1 ± 2.1 (p <0.0001). The interaction by treatment by time was not significant. The number of days of severe drinking as measured by the AUDIT-3 score was also significantly reduced: from 2.7 ± 0.9 to 1.6 ± 1.1 for 40 mg extract mixture / kg and 3.0 ± 0. It decreased from 8 to 2.2 ± 1.1 (p> .0001). The treatment interaction with time was not significant.

4.5 Summary of results Alcohol consumption as measured by the AUDIT QF (amount-frequency) score was significantly reduced for those who received the extract composition.

Example 5 : Raphanus extract increased brain dopamine levels in rats.

Materials and Methods 2.1. Experimental Animals Male Wistar rats (250-300 g, Amman-Jordan) were used throughout the study (8 rats for each experiment). Animals were housed in groups of 4 animals / cage with a 12/12 hour light cycle (lighted at 07.00 am) with food and water freely available. Animals were randomly assigned to different groups in the experiment. All experiments were performed according to standard ethical guidelines and approved by the local ethics committee (Medical University Animal Experiment Committee, 81/02, 2011, 1011 (University of Petra, Jordan, Amman)).

2.2. Drugs Fluoxetine hydrochloride [N-methyl-3-[(4-trifluoromethyl) phenoxy] -3-phenylpropylamine hydrochloride] and desipramine hydrochloride [10-11-dihydro-N-methyl-5H-dibenz (Z) [B, f] azepine-5-propanamine hydrochloride] (TOCRIS Bioscience, UK) was dissolved in sterile saline and administered intraperitoneally at a concentration of 1 ml / kg; the extract was prepared immediately before use. Saline was administered to the control group.

2.3. Plant material The extract of the genus Fanus satius was prepared in Jordan. In order to prepare the extract, 100 g of dried and milled stigma was extracted by cold immersion with 1000 ml of distilled water. The extract was dried at 35 ° C. to 40 ° C., and the yield of extraction was 23 mg lyophilized powder per 100 mg dry stigma. The extract was dissolved in normal saline and immediately administered to the animals.

2.4. 30 minutes after injection of the preparation drug and / or extracts of the brain, the animals were killed in _two boxes CO, cut neck by guillotine, experts removed their brains in less than 1 minute. The brain was homogenized in a Falcon tube containing 10 ml of cold (0 ° C.) sterile saline and centrifuged at 3000 rpm / min for 5 minutes at 4 ° C. The supernatant was used for subsequent neurotransmitter detection by ELISA. Based on previous studies, an interval time of 30 minutes was selected; this time was considered sufficient for the action of the extract.

2.5. Statistical analysis Data are expressed as mean of neurotransmitter concentrations ± standard error of the mean (SEM). One-way analysis of variance (one-way ANOVA) 3.

3. Results 3.1 Effect of Raphanus Extract on Brain Serotonin Concentrations To Racerus Extract at Different Doses (2, 8, 32, 64, 128 and 256 mg / kg, ip) of Brain Serotonin The action of was tested. Saline (1 ml / kg, ip) or fluoxetine (10 mg / kg, ip), desipramine (50 mg / kg, ip), Raphanus extract (different concentrations) And sacrificed after 30 minutes. One-way ANOVA showed that fluoxetine could significantly increase brain serotonin levels, but neither desipramine nor Raphanus extract could increase brain serotonin levels.

3.2 Effect of Raphanus Extract on Brain Dopamine Concentrations Our results indicate that fluoxetine (10 mg / kg, ip) and desipramine (50 mg / kg, ip) are in the brain dopamine concentrations. It was shown that can be increased.

  Interestingly, Raphanus extracts can increase dopamine levels in the brain in a dose-dependent manner, 256 mg / kg, i. p. The extract dose is the most potent in this study.

3.3 Effect of Raphanus Extract on Brain Glutamate Concentration In the final part of the experiment, the effect of Rafanus extract on brain glutamate concentration was examined. The results showed that there was a variation in brain glutamate levels in dependence on the extract dose. The extract can be, for example, 264 mg / kg, i.e. p. Was used to significantly increase the glutamate concentration in the brain.

Claims (15)

Less than:
a) An extract of a plant belonging to the genus Raphanus, wherein said extract is obtained by extracting at least aerial roots, seeds and / or bulbs with a hydrophilic, medium polarity and / or lipophilic solvent Can or is obtained;
b) extracts of plants belonging to the genus Theobroma, wherein said extracts can be obtained or obtained by extracting at least fruits with hydrophilic and / or moderately polar solvents; and c ) Extracts of plants belonging to the genus Passiflora, wherein said extracts can be obtained or obtained by extracting at least flowers with hydrophilic, medium polarity and / or lipophilic solvents;
A composition comprising The solvent of a) is selected from the group consisting of water, alcohol, water / alcohol mixture, ketone, water / ketone mixture, CO ₂ , ethyl acetate, hexane and chlorinated forms thereof; and / or b) above The composition of claim 1, wherein the solvent is selected from the group consisting of water, alcohol, water / alcohol mixtures, ketones and water / ketone mixtures.   An extract of said a) having a drug-extract ratio of 4-7.5: 1, an extract of said b) having a drug-extract ratio of 3-8: 1 and 5-7: 1 The extract of c) having a drug-extract ratio is about 0.5 to about 5 parts of the extract of a), about 2.75 to about 4 parts of b) in the composition. 3. A composition according to claim 1 or 2 present in an extract and a ratio of about 2.5 to about 5.5 parts of said extract c). Less than:
d) an extract of a plant belonging to the genus Crocus, wherein said extract can be obtained or obtained by extracting at least flowers with a hydrophilic, medium polarity and / or lipophilic solvent;
The composition according to any one of claims 1 to 3, further comprising:   An extract of said a) having a drug-extract ratio of 4 to 7.5: 1, an extract of said b) having a drug-extract ratio of 3 to 8: 1, of 5 to 7: 1 About 0.5 to about 4 parts of the extract of c) having a drug-extract ratio and the extract of d) having a drug-extract ratio of 0.5-5: 1 in the composition. About 2.5 to about 3 parts of the extract of b), about 2.5 to about 5.25 parts of the extract of c), and about 0.5. 5. The composition of claim 4 present in a ratio of about 3.75 parts of the extract of d).   The extract of a), the extract of b), the extract of c) and the extract of d) are about 2.5 parts of the extract of the a) in the composition, 6. A ratio of about 3 parts of the extract of b), about 2.5 parts of the extract of c) and about 1.5 parts of the extract of d). Composition.   The composition of any one of claims 1-6, wherein the composition further comprises olive oil.   The composition according to any one of claims 1 to 7, which is a pharmaceutical composition.   9. Composition according to claim 8, for use in opioid abuse, opioid dependence, alcohol abuse and / or alcohol dependence treatment and / or in the treatment of opioid and / or alcohol withdrawal symptoms. object.   10. A composition for use according to claim 9, wherein the composition is to be administered at a dose of about 18.5 to about 77.5 mg / kg per day.   11. A composition for use according to claim 10, wherein said dose is to be administered for at least 2 weeks. A method for producing a composition comprising an extract of a plant belonging to the genus Raphanus and an extract of a plant belonging to the genus Theobroma, comprising the following steps:
a) extracting at least aerial roots, seeds and / or bulbs of a plant of the genus Raphanus with a hydrophilic, moderately polar and / or lipophilic solvent;
b) extracting at least the fruit of the Theobroma plant with a hydrophilic and / or medium polar solvent; and c) combining the extract of step a) with the extract of step b);
And thereby producing said composition comprising an extract of a plant belonging to the genus Raphanus and an extract of a plant belonging to the genus Theobroma. 15. The method of claim 14, further comprising the following steps:
d) extracting at least the flowers of a plant belonging to the genus Passiflora with a hydrophilic, medium polarity and / or lipophilic solvent; and / or e) at least the flowers of a plant belonging to the genus Crocus with hydrophilic, medium Extraction with polar and / or lipophilic solvents of
Before step c) (in which case the extract of step d) and / or the extract of step e) is combined with the extract of steps a) and b) above), or after step c) (In which case the extract of step d) and / or the extract of step e) is combined in a further step f) with the composition of step c)), whereby an extract of the plant of the genus Raphanus, theobroma Said method for producing a composition comprising an extract of a plant, an extract of a plant of the genus Passiflora and / or an extract of a plant of the genus Crocus.   The composition according to any one of claims 1 to 8, wherein the plant belonging to the genus Raphanus is a Raphanus satius plant; and / or the plant belonging to the genus Theobroma is a Theobroma cacao plant. 14. A composition for use according to any one of the above, or a method according to claim 12 or 13.   The composition according to any one of claims 1 to 8, wherein the plant belonging to the genus Passiflora is a Passiflora incarnata plant; and / or the plant belonging to the genus Crocus is a Crocus satius plant. 14. A composition for use according to any one of -11 or a method according to claim 13.